1-alkyl-2-hydroxy-2-trifluoromethyl ethylamines

ABSTRACT

The invention concerns pharmaceutically useful trifluoromethyl ketone substituted di-, tri- and tetra-peptide derivatives of the formulae Ia, Ib, Ic set out hereinafter, and salts thereof, which are inhibitors of human leukocyte elastase. Also described herein are pharmaceutical compositions containing a peptide derivative and processes and intermediates for use in the manufacture of the peptide derivatives.

This application is a divisional application of application Ser. No.07/491,757, filed on Mar. 9, 1990, and now U.S. Pat. No. 5,194,588,which was a divisional application of Ser. No. 07/005,538, filed on Jan.20, 1987, and now U.S. Pat. No. 4,910,190, which was itself acontinuation-in-part of application 06/821,150, filed on Jan. 21, 1986,and now abandoned.

The present invention relates to certain trifluoromethyl ketonesubstituted peptide derivatives which are human leukocyte elastase (HLE)inhibitors making them useful whenever such inhibition is desired suchas for research tools in pharmacological, diagnostic and related studiesand in the treatment of tissue degenerative diseases such as pulmonaryemphysema, atherosclerosis, rheumatoid arthritis and osteo arthritis inwarm blooded animals. The invention also includes intermediates usefulin the synthesis of these peptide derivatives, processes for preparingthem, pharmaceutical compositions containing such peptide derivativesand methods for their use.

The substituted peptides of the present invention may be represented bythe formulae Ia, Ib and Ic (set out hereinbelow proceeding the Exampleswith other formulae denoted by Roman numerals) wherein

R¹ is alkyl;

R² and R⁵ are alkyl, substituted alkyl, aryl, aralkyl, substitutedaralkyl or substituted aryl;

R³ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,alkenyl, substituted alkenyl, aryl, substituted aryl, aralkyl,substituted aralkyl, an aliphatic heterocycle, substituted aliphaticheterocycle, an aromatic heterocycle or a substituted aromaticheterocycle;

R⁴ and R⁶ are hydrogen or methyl;

A is selected from the group consisting of ##STR1## and

n is 0, 1 or 2;

and, where appropriate, the acid- and base-addition salts thereof.

Compounds of formulae Ia, Ib and Ic are referred to herein asdipeptides, tripeptides and tetrapeptides, respectively.

The compounds of the invention include those wherein

R¹ is an alkyl group containing from 1 to 5 carbon atoms, and morepreferably from 2 to 5 carbons;

R² and R⁵ are each selected independently from the group consisting of:

(I) an alkyl group containing from 1 to 10 carbons;

(II) an alkyl group containing from 1 to 6 carbon atoms substituted byat least one member selected from the group consisting of:

(a) hydroxy;

(b) amino;

(c) alkylamino containing from 1 to 6 carbons;

(d) dialkylamino wherein each alkyl group contains from 1 to 6 carbons;

(e) alkanoyl containing from 1 to 6 carbons;

(f) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbons;

(g) aralkanoyl containing 8 to 13 carbons;

(h) amido which may be attached to the alkyl group via either a nitrogenor carbon of said amido;

(i) alkylcarbonylamino wherein the alkyl group contains from 1 to 6carbons;

(j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 6carbons;

(k) arylcarbonylamino wherein the aryl group contains 6, 10 or 12carbons;

(l) aralkylcarbonylamino wherein the aralkyl group contains from 7 to 13carbons;

(m) arylaminocarbonyl wherein the aryl group contains 6, 10 or 12carbons;

(n) aralkylaminocarbonyl wherein the aralkyl group contains from 7 to 13carbons;

(o) carboxy;

(p) aryloxycarbonyl wherein the aryl group contains 6, 10 or 12 carbons;

(q) aralkoxycarbonyl wherein the aralkoxy group contains from 7 to 13carbons;

(r) alkanoyloxy containing from 1 to 6 carbons;

(s) aroyloxy wherein the aryl portion contains 6, 10 or 12 carbons;

(t) aralkanoyloxy containing from 8 to 14 carbons;

(u) alkylsulfonamido wherein the alkyl group contains from 1 to 6carbons;

(v) aralkylsulfonamido wherein the aralkyl group contains from 7 to 13carbons;

(w) arylsulfonamido wherein the aryl group contains 6, 10 or 12 carbons;

(x) acylsulfonamido (i.e., acylaminosulfonyl and sulfonylaminocarbonyl)(1 to 15 carbons) including acylsulfonamido wherein the acyl groupcontains 1 to 7 carbons when it is the terminal portion of theacylsulfonamide and provided that when the acylsulfonamido contains anaryl the aryl may be further substituted by a member selected fromfluoro, chloro, bromo, iodo and nitro;

(y) alkoxycarbonyl wherein the alkoxy group contains from 1 to 6carbons;

(z) aralkoxycarbonylamino containing from 8 to 13 carbons (e.g.,benzyloxycarbonyl amino);

(aa) aryloxycarbonylamino wherein the aryloxy group contains 6, 10 or 12carbons;

(bb) alkoxycarbonylamino wherein the alkyloxy group contains from 1 to 6carbons;

(cc) aryl containing 6, 10 or 12 carbons (e.g., phenyl, biphenyl,naphthyl);

(dd) aryl containing 6, 10 or 12 carbons and substituted by 1 to 3members selected from the group consisting of chloro, bromo, iodo,fluoro, trifluoromethyl, hydroxy, alkyl (1 to 6 carbons), alkoxy (1 to 6carbons), alkoxycarbonyl (1 to 6 carbons), carboxy, 5-tetrazolo, andacylsufonamido (i.e. acylaminosulfonyl and sulfonylaminocarbonyl) (1 to15 carbons) and provided that when the acylsulfonamido contains an arylthe aryl may be further substituted by a member selected from fluoro,chloro, bromo, iodo and nitro;

(ee) cycloalkyl containing from 3 to 15 carbons (e.g., cyclohexyl,adamantyl, norbornyl);

(ff) alkylureido wherein the alkyl group contains from 1 to 6 carbons;

(gg) aralkylureido containing from 8 to 13 carbons;

(hh) arylureido wherein the aryl group contains 6, 10 or 12 carbons; and

(III) an aryl group of 6 carbons, e.g. phenyl;

R³ is selected from the group consisting of:

(I) an alkyl group containing from 1 to 12 carbons;

(II) an alkyl group containing from 1 to 12 carbons and from 1 to 4hetero atoms each of which is selected independently from the groupconsisting of nitrogen and oxygen;

(III) an alkyl group containing from 1 to 12 carbons and, optionally, 1to 4 hetero atoms each of which is selected independently from the groupconsisting of nitrogen and oxygen, and substituted on at least one ofcarbon or nitrogen by 1 to 3 members selected independently from thegroup consisting of:

For carbon:

(a) hydroxy, provided that it may not be on a carbon directly bonded toA;

(b) amino, provided that it may not be on a carbon directly bonded to A;

(c) alkylamino containing from 1 to 6 carbons, provided that it may notbe on a carbon directly bonded to A;

(d) dialkylamino wherein each alkyl group contains from 1 to 6 carbons,provided that it may not be on a carbon directly bonded to A;

(e) alkanoyl containing from 1 to 6 carbons;

(f) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbons;

(g) aralkanoyl containing 8 to 13 carbons;

(h) amido which may be attached to the alkyl group via either a nitrogenor carbon of said amido;

(i) alkylcarbonylamino wherein the alkyl group contains from 1 to 6carbons;

(j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 6carbons;

(k) arylcarbonylamino wherein the aryl group contains 6, 10 or 12carbons;

(k)-(1) arylcarbonylamino wherein the aryl group contains 6, 10 or 12carbons and is substituted by a member selected from carboxy,alkoxycarbonyl, where alkoxy is 1 to 3 carbons, 5-tetrazolo, andacylsulfonamido (i.e. acylaminosulfonyl and sulfonylaminocarbonyl)containing 1 to 15 carbons and provided that when the acylsulfonamidocontains an aryl the aryl may be further substituted by a memberselected from fluoro, chloro, bromo, iodo and nitro;

(l) aralkylcarbonylamino wherein the aralkyl group contains from 7 to 13carbons;

(l)-(1) aralkylcarbonylamino wherein the aralkyl group contains 7 to 13carbons and is substituted on the aryl portion by a member selected fromcarboxy, alkoxycarbonyl, where the alkoxy has 1 to 3 carbons,5-tetrazolo, and acylsulfonamido (i.e., acylaminosulfonyl andsulfonylaminocarbonyl) containing 1 to 15 carbons and provided that whenthe acylsulfonamido contains an aryl the aryl may be further substitutedby a member selected from fluoro, chloro, bromo, iodo and nitro;

(m) arylaminocarbonyl wherein the aryl group contains 6, 10 or 12carbons;

(n) aralkylaminocarbonyl wherein the aralkyl group contains from 7 to 13carbons;

(o) carboxy;

(p) aryloxycarbonyl wherein the aryl group contains 6, 10 or 12 carbons;

(q) aralkoxycarbonyl wherein the aralkoxy group contains from 7 to 13carbons;

(r) alkanoyloxy containing from 1 to 6 carbons;

(s) aroyloxy wherein the aryl portion contains 6, 10 or 12 carbons;

(t) aralkanoyloxy containing from 8 to 13 carbons;

(u) alkylsulfonamido wherein the alkyl group contains from 1 to 6carbons;

(u)-(1) cycloalkylsulfonamido wherein the cycloalkyl portion contains 3to 15 carbons (e.g., cyclohexyl, adamantyl, norbornyl);

(v) aralkylsulfonamido wherein the aralkyl group contains from 7 to 13carbons;

(w) arylsulfonamido wherein the aryl group contains 6, 10 or 12 carbons;

(x) acylsulfonamido (i.e., acylaminosulfonyl and sulfonylaminocarbonyl)(1 to 15 carbons) including acylsulfonamido wherein the acyl groupcontains 1 to 7 carbons when it is the terminal portion of theacylsulfonamide, and provided that when the acylsulfonamido contains anaryl the aryl may be further substituted by a member selected fromfluoro, chloro, bromo, iodo and nitro;

(y) alkoxycarbonyl wherein the alkoxy group contains from 1 to 6carbons;

(z) aralkoxycarbonylamino containing from 8 to 13 carbons (e.g.,benzyloxycarbonylamino);

(z)-(1) aralkylaminocarbonyloxy containing 8 to 13 carbons;

(z)-(2) aryloxy wherein the aryl contains 6, 10 or 12 carbons;

(z)-(3) aryloxy wherein the aryl contains, 6, 10 or 12 carbons and issubstituted by a member selected from aminocarbonyl, aminocarbonylalkylwhere the alkyl has 1 to 3 carbons, alkoxy carbonyl having 2 to 4carbons, and carboxy;

(aa) aryloxycarbonylamino wherein the aryloxy group contains 6, 10 or 12carbons;

(aa)-(1) arylaminocarbonyloxy wherein the aryl group contains 6, 10 or12 carbons;

(bb) alkoxycarbonylamino wherein the alkyloxy group contains from 1 to 6carbons;

(bb)-(1) alkoxycarbonylamino wherein the alkoxy group contains 1 to 6carbons and is optionally bonded on carbon to a carbon of an aromaticheterocyclic group as described in (gg) under R³ ;

(bb)-(2) alkoxycarbonylamino wherein the alkoxy group contains 1 to 6carbons substituted by an aliphatic heterocyclic group as described in(ff) under R³ ;

(bb)-(3) aryloxyalkylcarbonyl amino wherein the aryl contains 6 or 10carbons and the alkyl has 1 to 6 carbons;

(bb)-(4) alkylaminocarbonyloxy wherein the alkyl group contains 1 to 6carbons;

(cc) aryl containing 6, 10 or 12 carbons (e.g., phenyl, naphthyl,biphenyl);

(cc)-(1) aryloxy containing 6, 10 or 12 carbons;

(dd) aryl containing 6, 10 or 12 carbons and substituted by 1 to 3members independently selected from the group consisting of chloro,bromo, iodo, fluoro, hydroxy, trifluoromethyl, alkyl (1 to 6 carbons),alkoxy (1 to 6 carbons), alkoxycarbonyl (2 to 6 carbons), carboxy,aminocarbonylalkyl (2 to 6 carbons), aminocarbonyl, 5-tetrazolo, andacylsulfonamido (i.e., acylaminosulfonyl and sulfonylaminocarbonyl) (1to 15 carbons), and provided that when the acylsulfonamido contains anaryl the aryl may be further substituted by a member selected fromfluoro, chloro, bromo, iodo and nitro;

(dd)-(1) aryloxy containing 6, 10 or 12 carbons and substituted oncarbon by 1 to 3 members independently selected from the groupconsisting of chloro, bromo, iodo, fluoro, hydroxy, trifluoromethyl,alkyl (1 to 6 carbons), alkoxy (1 to 6 carbons), alkoxycarbonyl (2 to 6carbons), carboxy, aminocarbonylalkyl (2 to 6 carbons), aminocarbonyl,5-tetrazolo, acylsulfonamido (i.e., acylaminosulfonyl andsulfonylaminocarbonyl) (1 to 15 carbons) and provided that when theacylsulfonamido contains an aryl the aryl may be further substituted bya member selected from fluoro, chloro, bromo, iodo and nitro;

(ee) cycloalkyl containing from 3 to 15 carbons (e.g., cyclohexyl,adamantyl, norbornyl);

(ee)-(1) cycloalkyloxy containing from 3 to 15 carbons;

(ff) an aliphatic heterocyclic group of at least 4 atoms containing from1 to 5 carbons and from 1 to 4 hetero atoms each of which is selectedindependently from the group consisting of nitrogen and oxygen (e.g.,morpholine, piperazine), wherein the aliphatic heterocyclic group mayoptionally contain 1 or 2 double bond(s), which aliphatic heterocyclicgroup may be substituted at any nitrogen with an alkyl group containingfrom 1 to 6 carbons, an alkanoyl group containing from 1 to 6 carbons,an aryloxycarbonyl group wherein the aryl group contains 6, 10 or 12carbon atoms, an aralkyloxycarbonyl group wherein the aralkyl groupcontains from 7 to 13 carbons or an alkoxycarbonyl group wherein thealkyl group contains from 1 to 6 carbons;

(ff)-(1) an aliphatic heterocyclic oxy group wherein the oxy link the isbonded directly to a carbon atom of the aliphatic heterocyclic group ofat least 5 atoms containing from 1 to 5 carbons and from 1 to 4 heteroatoms each of which is selected independently from the group consistingof nitrogen and oxygen, (e.g., morpholine, piperazine), wherein thealiphatic heterocyclic group may optionally contain 1 or 2 doublebond(s), which aliphatic heterocyclic group may be substituted at anynitrogen with an alkyl group containing from 1 to 6 carbons, an alkanoylgroup containing from 1 to 6 carbons, an aryloxycarbonyl group whereinthe aryl group contains 6, 10 or 12 carbons, an aralkyloxycarbonyl groupwherein the aralkyl group contains from 7 to 13 carbons or analkoxycarbonyl group wherein the alkyl group contains from 1 to 6carbons;

(gg) an aromatic heterocyclic group of from 1 to 15 carbons and from 1to 4 heteroatoms each of which is selected independently from the groupconsisting of sulfur, nitrogen and oxygen and which form 1 to 3 five orsix-membered rings at least one of which is aromatic, and optionally,wherein up to 3 carbons of the aromatic ring(s) may be substituted witha member of the group consisting of fluoro, chloro, bromo, iodo,trifluoromethyl, alkyl containing from 1 to 6 carbons, alkoxy containingfrom 1 to 6 carbons, alkanoyl containing from 2 to 6 carbons, carboxy,aminocarbonylalkyl (2 to 6 carbons) and aminocarbonyl, and providedfurther that any nitrogen atom may be substituted by an alkyl groupcontaining from 1 to 6 carbon atoms;

(gg)-(1) an aromatic heterocyclic oxy group wherein the oxy link isbonded directly to a carbon of an aromatic heterocyclic group of from 1to 15 carbons and from 1 to 4 heteroatoms each of which is selectedindependently from the group consisting of sulfur, nitrogen and oxygenand which form 1 to 3 five or six-membered rings at least one of whichis aromatic, and optionally, wherein up to 3 carbons of the aromaticring(s) may be substituted with a member of the group consisting offluoro, chloro, bromo, iodo, trifluoromethyl, alkyl containing from 1 to6 carbons, alkoxy containing from 1 to 6 carbons, alkanoyl containingfrom 2 to 6 carbons, carboxy, aminocarbonylalkyl (2 to 6 carbons) andaminocarbonyl, and provided further that any nitrogen atom may besubstituted by an alkyl group containing from 1 to 6 carbons;

(hh) alkylureido wherein the alkyl group contains from 1 to 6 carbonatoms;

(hh)-(1) cycloalkylureido wherein the cycloalkyl group contains 3 to 15carbons;

(ii) aralkylureido wherein the aralkyl group contains from 7 to 13carbons;

(jj) arylureido wherein the aryl group contains 6, 10 or 12 carbons;

(jj)-(1) arylureido wherein the aryl group contains 6, 10 or 12 carbonsand is substituted by 1 to 3 members selected independently from thegroup consisting of chloro, bromo, iodo, fluoro, hydroxy,trifluoromethyl, alkyl (1 to 6 carbons), alkoxy (1 to 6 carbons),alkoxycarbonyl (2 to 6 carbons), carboxy, aminocarbonylalkyl (2 to 6carbons), aminocarbonyl, 5-tetrazolo, and acylsulfonamido (i.e.,acylaminosulfonyl and sulfonylaminocarbonyl) (1 to 15 carbons) includingacylsulfonamido wherein the acyl group contains 1 to 7 carbons when itis the terminal portion of the acylsulfonamide and provided that whenthe acylsulfonamido contains an aryl the aryl may be further substitutedby a member selected from fluoro, chloro, bromo, iodo and nitro;

For nitrogen:

(a) alkyl of 1 to 3 carbons;

(b) alkanoyl containing from 2 to 6 carbon atoms;

(c) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbons;

(d) aralkanoyl containing 8 to 14 carbons;

(e) formyl;

(f) an aliphatic heterocyclic group wherein the amino link is bondeddirectly to a carbon of an aliphatic heterocyclic group defined in (ff)for the carbon substituents;

(g) an aromatic heterocyclic group wherein the amino link is bondeddirectly to a carbon of the aromatic heterocyclic group defined in (gg)for the carbon substituents;

(IV) an aryl group containing 6, 10 or 12 carbons;

(V) an aryl group containing 6, 10 or 12 carbons suitably substituted by1 to 3 members selected independently from the group consisting offluoro, chloro, bromo, iodo, trifluoromethyl, hydroxy, alkyl containingfrom 1 to 6 carbons, alkoxy containing from 1 to 6 carbons,alkoxycarbonyl containing from 2 to 6 carbons, carboxy,alkylcarbonylamino wherein the alkyl group contains 1 to 6 carbons,5-tetrazolo, and acylsulfonamido (i.e., acylaminosulfonyl andsulfonylaminocarbonyl) containing from 1 to 15 carbons, and providedthat when the acylsulfonamido contains an aryl the aryl may be furthersubstituted by a member selected from fluoro, chloro, bromo, iodo andnitro;

(VI) a cycloalkyl group containing from 3 to 15 carbons (e.g.,cyclohexyl, adamantyl, norbornyl);

(VI)-(1) a cycloalkyl group containing from 3 to 15 carbons (e.g.,cyclohexyl, adamantyl, norbornyl), substituted by a member selected fromthe group consisting of carboxy and alkoxycarbonyl wherein the alkoxygroup contains 1 to 4 carbons;

(VII) an aliphatic heterocyclic group of at least 5 atoms containingfrom 1 to 5 carbons and from 1 to 4 hetero atoms each of which isselected independently from the group consisting of nitrogen and oxygen,(e.g., morpholine, piperazine) which may be substituted at any nitrogenwith a member selected from the group consisting of an alkyl groupcontaining from 1 to 6 carbon atoms, an alkanoyl group containing from 1to 6 carbons, an aryloxycarbonyl group wherein the aryl group contains6, 10 or 12 carbons, an aralkoxycarbonyl group wherein the aralkyl groupcontains from 7 to 13 carbons and an alkoxycarbonyl group containingfrom 2 to 7 carbons, provided that when A is OCO or NHCO then A must bebonded to a carbon atom of the aliphatic heterocyclic group;

(VIII) an aromatic heterocyclic group of from 1 to 15 carbons and from 1to 4 heteroatoms each of which is selected independently from the groupconsisting of sulfur, nitrogen and oxygen, and which form 1 to 3 five orsix-membered rings at least one of which is aromatic, and optionally,wherein up to 3 carbons of the aromatic ring(s) may be substituted atany carbon atom with a member of the group consisting of fluoro, chloro,bromo, iodo, trifluoromethyl, alkyl containing from 1 to 6 carbons,alkoxy containing from 1 to 6 carbons, alkanoyl containing from 2 to 6carbons, carboxy, and provided further that any nitrogen may besubstituted by an alkyl group containing from 1 to 6 carbons, providedthat when A is OCO or NHCO then A must be bonded to a carbon of thearomatic heterocycle;

(IX) an alkenyl group of 2 to 10 carbons, having at least one doublebond; and

(X) an alkenyl group of 2 to 10 carbons, having at least one double bondand substituted by a member selected from the group consisting of

(a) aryl of 6 or 10 carbons;

(b) aryl of 6 or 10 carbons substituted by 1 to 3 members selectedindependently from the group consisting of chloro, bromo, iodo, fluoro,hydroxy, trifluoromethyl, alkyl (1 to 6 carbons), alkoxy (1 to 6carbons), alkoxycarbonyl (2 to 6 carbons), carboxy, 5-tetrazolo, andacylsulfonamido (i.e., acylaminosulfonyl and sulfonylaminocarbonyl) (1to 15 carbons) and provided that when the acylsulfonamido contains anaryl the aryl may be further substituted by a member selected fromfluoro, chloro, bromo, iodo and nitro; and

(c) ureidocarbonyl;

R⁴ and R⁶ are each independently selected from hydrogen or methyl;

n is 0, 1 or 2; and

A is selected from the group consisting of ##STR2## and whereappropriate, the acid- and base-addition salts thereof.

Particular values for compounds of the invention include the followingmembers of the groups defined above:

R¹ is an alkyl group containing 3 carbons;

R² and R⁵ are each selected independently from the group consisting of:

(I) an alkyl group containing from 1 to 4 carbons;

(II) an alkyl group containing from 1 to 4 carbons substituted by atleast one member selected from the group consisting of:

(e) alkanoyl containing from 1 to 3 carbons;

(f) arylcarbonyl wherein the aryl contains 6 or 10 carbons (e.g., phenylor naphthyl);

(g) aralkanoyl containing 8 carbons (e.g., phenylacetyl);

(h) amido which may be attached to the alkyl group via either a nitrogenor carbon of said amido;

(i) alkylcarbonylamino wherein the alkyl group contains from 1 to 2carbons;

(j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 2carbons;

(k) arylcarbonylamino wherein the aryl group contains 6 carbons (e.g.,phenyl);

(l) aralkylcarbonylamino wherein the aralkyl group contains 7 carbons;

(m) arylaminocarbonyl wherein the aryl group contains 6 carbons;

(n) aralkyaminocarbonyl wherein the aralkyl group contains 7 carbons;

(o) carboxy;

(p) aryloxycarbonyl wherein the aryl group contains 6 carbons;

(q) aralkoxycarbonyl wherein the aralkoxy group contains 7 carbons;

(r) alkanoyloxy containing from 1 to 2 carbons;

(s) aroyloxy wherein the aryl portion contains 6 carbons;

(t) aralkanoyloxy containing 8 carbons;

(u) alkylsulfonamido wherein the alkyl group contains from 1 to 6carbons;

(v) aralkylsulfonamido wherein the aralkyl group contains from 7 to 13carbons (e.g., 1-naphthylmethylsulfonylamino or4-phenylbutylsulfonylamino);

(w) arylsulfonamido wherein the aryl group contains 6 or 10 carbons;

(x) acylsulfonamido containing 1 to 15 carbons (e.g.phenylsulfonylaminocarbonyl);

(y) alkoxycarbonyl wherein the alkoxy group contains from 1 to 2carbons;

(z) aralkoxycarbonylamino wherein the aralkoxy group contains 7 carbons(e.g., benzyloxycarbonylamino);

(aa) aryloxycarbonylamino wherein the aryloxy group contains 6 carbons;

(bb) alkoxycarbonylamino wherein the alkyloxy group contains from 1 to 3carbons;

(cc) aryl containing 6 or 10 carbons (e.g., phenyl or naphthyl);

(dd) aryl containing 6 or 10 carbons and substituted by 1 to 3 membersselected from the group consisting of chloro, bromo, iodo, fluoro,trifluoromethyl, hydroxy, alkyl (1 to 2 carbons), alkoxy (1 to 2carbons), alkoxycarbonyl (2 to 3 carbons), carboxy, 5-tetrazolo andacylsufonamido (1 to 15 carbons);

(ee) cycloalkyl containing from 3 to 15 carbons (e.g., cyclohexyl,adamantyl, norbornyl).

(ff) alkylureido wherein the alkyl group contains from 1 to 2 carbons;

(gg) aralkylureido wherein the aralkyl group contains 7 carbons;

(hh) arylureido wherein the aryl group contains 6 or 10 carbons; and

(III) an aryl group of 6 carbons;

R³ is selected from the group consisting of:

(I) an alkyl group containing from 1 to 12 carbons;

(II) an alkyl group containing from 1 to 12 carbons and from 1 to 4hetero atoms each of which is selected independently from the groupconsisting of nitrogen and oxygen;

(III) an alkyl group containing from 1 to 12 carbons and, optionally, 1to 4 hetero atoms each of which is selected independently from the groupconsisting of nitrogen and oxygen, and substituted on at least one ofcarbon or nitrogen by 1 to 3 members selected independently from thegroup consisting of:

For carbon:

(e) alkanoyl containing from 1 to 6 carbons;

(f) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbons;

(g) aralkanoyl containing 8 to 13 carbons;

(h) amido which may be attached to the alkyl group via either a nitrogenor carbon of said amido;

(i) alkylcarbonylamino wherein the alkyl group contains from 1 to 6carbons;

(j) alkylaminocarbonyl wherein the alkyl group contains from 1 to 6carbons;

(k) arylcarbonylamino wherein the aryl group contains 6 or 10 carbons;

(k)-(1) arylcarbonylamino wherein the aryl group contains 6 or 10carbons and is substituted by a member selected from carboxy,alkoxycarbonyl, where alkoxy is 1 to 3 carbons, 5-tetrazolo, andacylsulfonamido containing 1 to 15 carbons;

(l) aralkylcarbonylamino wherein the aralkyl group contains from 7 to 13carbons;

(l)-(1) aralkylcarbonylamino wherein the aralkyl group contains 7 to 13carbons and is substituted on the aryl portion by a member selected fromcarboxy, alkoxycarbonyl, where the alkoxy has 1 to 3 carbons,5-tetrazolo, and acylsulfonamido containing 1 to 15 carbons;

(m) arylaminocarbonyl wherein the aryl group contains 6 or 10 carbons;

(n) aralkylaminocarbonyl wherein the aralkyl group contains from 7 to 13carbons;

(o) carboxy;

(p) aryloxycarbonyl wherein the aryl group contains 6 or 10 carbons;

(q) aralkoxycarbonyl wherein the aralkoxy group contains from 7 to 13carbons;

(r) alkanoyloxy containing from 2 to 3 carbons;

(s) aroyloxy wherein the aryl portion contains 6 or 10 carbons;

(t) aralkanoyloxy containing from 8 to 13 carbons;

(u) alkylsulfonamido wherein the alkyl group contains from 1 to 6carbons;

(u)-(1) cycloalkylsulfonamido wherein the cycloalkyl portion contains 3to 15 carbons (e.g., the cycloalkyl may be cyclohexyl, adamantyl,norbornyl), e.g., 1-adamantylsulfonylamido;

(v) aralkylsulfonamido wherein the aralkyl group contains from 7 to 13carbons;

(w) arylsulfonamido wherein the aryl group contains 6 or 10 carbons;

(x) acylsulfonamido containing 1 to 15 carbons;

(y) alkoxycarbonyl wherein the alkoxy group contains from 1 to 3carbons;

(z) aralkoxycarbonylamino containing from 8 to 13 carbons (e.g.,benzyloxycarbonylamino);

(z)-(1) aralkylaminocarbonyloxy wherein the aralkyl group contains 7 to13 carbons;

(z)-(2) aryloxy wherein the aryl contains 6, 10 or 12 carbons;

(z)-(3) aryloxy wherein the aryl contains 6, 10 or 12 carbons and issubstituted by a member selected from aminocarbonyl, aminocarbonylalkylwhere the alkyl has 1 to 3 carbons, alkoxycarbonyl having 2 to 4carbons, and carboxy;

(aa) aryloxycarbonylamino wherein the aryloxy group contains 6 or 10carbons;

(aa)-(1) arylaminocarbonyloxy wherein the aryl group contains 6 or 10carbons;

(bb) alkoxycarbonylamino wherein the alkyloxy group contains from 1 to 6carbons;

(bb)-(1) alkoxycarbonylamino wherein the alkoxy group contains 1 to 6carbons and is optionally bonded to a carbon of an aromatic heterocyclicgroup as described in (gg) under R³ ;

(bb)-(2) alkoxycarbonylamino wherein the alkoxy group contains 1 to 6carbons substituted by an aliphatic heterocyclic group as described in(ff) under R³ ;

(bb)-(3) aryloxyalkylcarbonylamino wherein the aryl contains 6 or 10carbons and the alkyl has 1 to 6 carbons;

(bb)-(4) alkylaminocarbonyloxy wherein the alkyl group contains 1 to 6carbons;

(cc) aryl containing 6 or 10 carbons (e.g., phenyl or naphthyl);

(cc)-(1) aryloxy containing 6 or 10 carbons;

(dd) aryl containing 6, 10 or 12 carbons and substituted by 1 to 3members independently selected from the group consisting of chloro,bromo, iodo, fluoro, hydroxy, trifluoromethyl, alkyl (1 to 6 carbons),alkoxy (1 to 6 carbons), alkoxycarbonyl (2 to 6 carbons), carboxy,aminocarbonylalkyl (2 to 6 carbons), aminocarbonyl, 5-tetrazolo, andacylsulfonamido (1 to 15 carbons);

(dd)-(1) aryloxy containing 6, 10 or 12 carbons and substituted by 1 to3 members independently selected from the group consisting of chloro,bromo, iodo, fluoro, hydroxy, trifluoromethyl, alkyl (1 to 6 carbons),alkoxy (1 to 6 carbons), alkoxycarbonyl (2 to 6 carbons), carboxy,acylsulfonamido (1 to 15 carbons), aminocarbonylalkyl (2 to 6 carbons),aminocarbonyl and 5-tetrazolo;

(ee) cycloalkyl containing from 3 to 15 carbons (e.g., cyclohexyl,adamantyl or norbornyl);

(ee)-(1) cycloalkyloxy containing from 3 to 15 carbons;

(ff) an aliphatic heterocyclic group of at least 5 atoms containing from1 to 5 carbons and from 1 to 4 hetero atoms each of which is selectedindependently from the group consisting of nitrogen and oxygen (e.g.,morpholine, piperazine), wherein the aliphatic heterocyclic group mayoptionally contain 1 or 2 double bond(s), which aliphatic heterocyclicgroup may be substituted at any nitrogen with an alkyl group containingfrom 1 to 6 carbons, an alkanoyl group containing from 2 to 6 carbons,an aryloxycarbonyl group wherein the aryl group contains 6, 10 or 12carbons, an aralkyloxycarbonyl group wherein the aralkyl group containsfrom 7 to 13 carbons or an alkoxycarbonyl group wherein the alkyl groupcontains from 1 to 6 carbons;

(ff)-(1) an aliphatic heterocyclic oxy group wherein the oxy link isbonded directly to a carbon of an aliphatic heterocyclic group of atleast 5 atoms containing from 1 to 5 carbons and from 1 to 4 heteroatoms each of which is selected independently from the group consistingof nitrogen and oxygen, wherein the aliphatic heterocyclic group mayoptionally contain 1 or 2 double bond(s), which aliphatic heterocyclicgroup may be substituted at any nitrogen with an alkyl group containingfrom 1 to 6 carbons, an alkanoyl group containing from 2 to 6 carbons,an aryloxycarbonyl group wherein the aryl group contains 6, 10 or 12carbons, an aralkyloxycarbonyl group wherein the aralkyl group containsfrom 7 to 13 carbons or an alkoxycarbonyl group wherein the alkyl groupcontains from 1 to 6 carbons (e.g., morpholine, piperazine);

(gg) an aromatic heterocyclic group of from 1 to 15 carbons and from 1to 4 heteroatoms each of which is selected independently from the groupconsisting of sulfur, nitrogen and oxygen and which form 1 to 2 five orsix-membered rings at least one of which is aromatic, and optionally,wherein up to 3 carbons of the aromatic ring(s) may be substituted witha member of the group consisting of fluoro, chloro, bromo, iodo,trifluoromethyl, alkyl containing methyl, alkoxy containing from 1 to 2carbons, alkanoyl containing from 2 to 3 carbons, carboxy,aminocarbonylalkyl (2 to 6 carbons) and aminocarbonyl, and providedfurther that any nitrogen atom may be substituted by an alkyl groupcontaining from 1 to 6 carbons;

(gg)-(1) an aromatic heterocyclic oxy group wherein the oxy link isbonded directly to a carbon atom of an aromatic heterocyclic group offrom 1 to 15 carbons and from 1 to 4 heteroatoms each of which isselected independently from the group consisting of sulfur, nitrogen andoxygen and which form 1 to 2 five or six-membered rings at least one ofwhich is aromatic, and optionally, wherein up to 3 carbons of thearomatic ring(s) may be substituted with a member of the groupconsisting of fluoro, chloro, bromo, iodo, trifluoromethyl, methyl,alkoxy containing from 1 to 2 carbons, alkanoyl containing from 2 to 3carbons, carboxy, aminocarbonylalkyl (2 to 6 carbons) and aminocarbonyl,and provided further that any nitrogen atom may be substituted by analkyl group containing from 1 to 6 carbons;

(hh) alkylureido wherein the alkyl group contains from 1 to 6 carbons;

(hh)-(1) cycloalkylureido wherein the cycloalkyl group contains 3 to 15carbons;

(ii) aralkylureido wherein the aralkyl group contains from 7 to 13carbons;

(jj) arylureido wherein the aryl group contains 6 or 10 carbons;

(jj)-(1) arylureido wherein the aryl group contains 6 or 10 carbons andis substituted by 1 to 3 members independently selected from the groupconsisting of chloro, bromo, iodo, fluoro, hydroxy, trifluoromethyl,alkyl (1 to 6 carbons), alkoxy (1 to 6 carbons), alkoxycarbonyl (2 to 6carbons), carboxy, acylsulfonamido (1 to 15 carbons), aminocarbonylalkyl(2 to 6 carbons), aminocarbonyl and 5-tetrazolo;

For nitrogen:

(a) alkyl of 1 to 3 carbons;

(b) alkanoyl containing from 2 to 6 carbons;

(c) arylcarbonyl wherein the aryl contains 6, 10 or 12 carbons;

(d) aralkanoyl containing 8 to 13 carbons;

(e) formyl;

(f) an aliphatic heterocyclic amino group wherein the amino link isbonded directly to a carbon of an aliphatic heterocyclic group definedin (ff) for the carbon substituents;

(g) an aromatic heterocyclic amino group wherein the amino link isbonded directly to a carbon of the aromatic heterocyclic group definedin (gg) for the carbon substituents;

(IV) an aryl group containing 6 or 10 carbons;

(V) an aryl group containing 6 or 10 carbons suitably substituted by 1to 3 members selected independently from the group consisting of fluoro,chloro, bromo, iodo, trifluoromethyl, alkyl containing from 1 to 6carbons, alkoxy containing from 1 to 6 carbons, alkoxycarbonylcontaining from 2 to 6 carbons, carboxy, alkylcarbonylamino wherein thealkyl group contains 1 to 6 carbons, 5-tetrazolo, and acylsulfonamidocontaining from 1 to 15 carbons (e.g.,4-[(4-chlorophenyl)sulfonylaminocarbonyl]phenyl or4-[(4-bromophenyl)sulfonylaminocarbonyl]phenyl);

(VI) a cycloalkyl group containing from 3 to 15 carbons (e.g.,cyclohexyl, adamantyl or norbornyl);

(VI)-(1) a cycloalkyl group containing from 3 to 15 carbons (e.g.,cyclohexyl, adamantyl or norbornyl), substituted by a member selectedfrom the group consisting of carbon and alkoxycarbonyl wherein thealkoxy group contains 1 to 4 carbons;

(VII) an aliphatic heterocyclic group of at least 5 atoms containingfrom 1 to 5 carbons and from 1 to 4 hetero atoms each of which isselected independently from the group consisting of nitrogen and oxygen,(e.g., morpholine, piperazine), which may be substituted at any nitrogenwith a member selected from the group consisting of methyl, an alkanoylgroup containing from 2 to 6 carbons, an aryloxycarbonyl group whereinthe aryl group contains 6 or 10 carbons, an aralkoxycarbonyl groupwherein the aralkyl group contains 7 carbons and an alkoxycarbonyl groupcontaining from 2 to 3 carbons, provided that when A is OCO or NHCO,then A must be bonded to a carbon of the aliphatic heterocyclic group;

(VIII) an aromatic heterocyclic group of from 1 to 15 carbons and from 1to 4 heteroatoms each of which is selected independently from the groupconsisting of sulfur, nitrogen and oxygen, and which form 1 to 2 five orsix-membered rings at least one of which is aromatic, and optionally,wherein up to 3 carbons of the aromatic ring(s) may be substituted atany carbon atom with a member of the group consisting of fluoro, chloro,bromo, iodo, trifluoromethyl, methyl, alkoxy containing from 1 to 2carbons, alkanoyl containing from 2 to 3 carbons, carboxy, and providedfurther that any nitrogen may be substituted by an alkyl groupcontaining from 1 to 6 carbons, provided that when A is OCO or NHCO thenA must be bonded to a carbon of the aromatic heterocycle;

(IX) an alkenyl group of 2 to 10 carbons, having at least one doublebond;

(X) an alkenyl group of 2 to 10 carbons, having at least one double bondand substituted by a member selected from the group consisting of

(a) aryl of 6 or 10 carbons;

(b) aryl of 6 or 10 carbons substituted by 1 to 3 members selectedindependently from the group consisting of chloro, bromo, iodo, fluoro,hydroxy, trifluoromethyl, alkyl (1 to 6 carbons), alkoxy (1 to 6carbons), alkoxycarbonyl (2 to 6 carbons), carboxy, acylsulfonamido (1to 15 carbons) and 5-tetrazolo; and

(c) ureidocarbonyl;

R⁴ and R⁶ are each hydrogen;

n=1; and

A is selected from the group consisting of ##STR3##

More particular values include:

R¹ selected to be isopropyl;

R² selected from the group consisting of:

(I) an alkyl group containing 2 to 3 carbons;

(II)

(q) ethyl substituted by aralkoxycarbonyl wherein the aralkoxy groupcontains 7 carbons;

(w) butyl substituted by an arylsulfonamido wherein the aryl portion has6 carbons;

(x) ethyl substituted by acylsulfonamido containing 7 carbons (e.g.,2-(phenylsulfonylaminocarbonyl)ethyl);

(z) butyl substituted by aralkyloxycarbonylamino wherein the aralkoxyportion contains 7 carbons, (e.g., benzyloxycarbonylamino);

(cc) methyl substituted by an aryl containing 6 carbons; and

(III) aryl containing 6 carbons;

R³ selected from the group consisting of:

(I) branched alkyl containing 4 carbons;

(II) an alkyl group containing 5 carbons and 2 oxygens;

(III)

(k) ethyl substituted by arylcarbonylamino wherein the aryl portioncontains 6 carbons;

(l) ethyl substituted by an aralkylcarbonylamino wherein the aralkylportion contains 13 carbons;

(n) ethyl substituted by aralkylaminocarbonyl wherein the alkyl contains7 carbons;

(o) an alkyl group containing 2 or 10 carbons and substituted bycarboxy;

(w) an alkyl group containing 5 carbons and substituted byarylsulfonamido wherein the aryl portion contains 6 carbons;

(x) ethyl substituted by an acylsulfonamido selected from the groupconsisting of 2-(methylsulfonylaminocarbonyl)ethyl,2-(phenylsulfonylaminocarbonyl)ethyl,2-[(1-adamantyl)sulfonylaminocarbonyl]ethyl, and2-[(1-naphthyl)sulfonylaminocarbonyl]ethyl;

(y) an alkyl group containing 2 or 10 carbons and substituted bymethoxycarbonyl;

(z) an alkyl group containing 2 to 5 carbons and substituted byaralkoxycarbonyl wherein the aralkoxy portion contains 7 carbons;

(aa) an alkyl containing 5 carbons and substituted byaryloxycarbonylamino wherein the aryloxy portion contains 6 carbons;

(bb) ethyl substituted by alkoxycarbonylamino wherein the alkyl groupcontains 4 carbons; and an alkyl containing 5 carbons and substituted byan alkyloxycarbonylamino wherein the alkoxy group contains 2 carbons andis substituted on the terminal carbon via a direct link to a carbon atomof an aromatic heterocycle containing 5 carbons and 1 nitrogen;

(bb)-(3) a propyl group substituted by an aryloxyalkylcarbonylaminowherein the aryl group contains 6 carbons and the alkyl group is methyl;

(cc) methyl or butyl substituted by aryl containing 6 carbons; and abranched alkyl group containing 5 carbons and substituted by 2 arylgroups each containing 6 carbons;

(dd) a member selected from the group consisting of an alkyl containing1 or 2 carbons and substituted with an aryl containing 6 carbons whereinthe aryl is further substituted by carboxy; methyl substituted by anaryl containing 6 carbons wherein the aryl is further substituted bymethoxycarbonyl; ethyl substituted by an aryl containing 6 carbonswherein the aryl is further substituted by ethoxycarbonyl; and ethylsubstituted by an aryl containing 6 carbons wherein the aryl is furthersubstituted by an acylsulfonamido containing 7 carbons;

(ee) ethyl substituted by a cycloalkyl containing 10 carbons, (e.g.,1-adamantylethyl);

(ff) ethyl substituted by an aliphatic heterocycle containing 4 carbons,1 nitrogen and 1 oxygen (e.g., 2-(4-morpholinyl)ethyl);

(gg) an alkyl containing 1 to 2 carbons and substituted by an aromaticheterocycle containing 4 carbons and 1 sulfur (e.g.,(2-thiophenyl)methyl or 2-(3-thiophenyl)ethyl); and ethyl substituted byan aromatic heterocycle containing 5 carbons and 1 nitrogen;

(jj)-(1) an alkyl group containing 5 carbons and substituted by anarylureido wherein the aryl portion contains 6 carbons and wherein thearyl portion is further substituted by ethoxycarbonyl or carboxy;

(zz) propyl substituted by aryloxy wherein the aryl contains 6 carbons;a branched alkyl group containing 5 carbons and substituted by 2 aryloxygroups each containing 6 carbons;

(zzz) methyl or propyl substituted by an aryloxy containing 6 carbonswherein the aryloxy is further substituted by aminocarbonyl; and methylsubstituted by an aryloxy containing 6 carbons wherein the aryloxy isfurther substituted by ethoxycarbonyl;

(IV) an aryl group containing 6 or 10 carbons, e.g., phenyl or naphthyl;

(V) an aryl group containing 6 carbons substituted by a member selectedfrom the group consisting of fluoro, hydroxy, carboxy, methoxy, ethoxy,methoxycarbonyl, ethoxycarbonyl, methylcarbonylamino, an acylsulfonamidocontaining 2 carbons, (e.g., 4-(methylsulfonaminocarbonyl)phenyl), anacylsulfonamido containing 7 carbons (e.g.,4-(phenylsulfonylaminocarbonyl)phenyl,4-[(4-chlorophenyl)sulfonylaminocarbonyl]phenyl, or[(4-bromophenyl)sulfonylaminocarbonyl]phenyl), an acylsulfonamidocontaining 11 carbons (e.g., 4(1-naphthylsulfonylaminocarbonylphenyl),an acylsulfonamido containing 14 carbons (e.g.,4-(4-bromophenylsulfonylamino(benzyl)carbonyl)phenyl); and an aryl groupcontaining 6 carbons and substituted by 2 chloros;

(VI) a cycloalkyl containing 10 carbons (e.g., 1-adamantyl);

(VI) -(1) a cycloalkyl containing 5 carbons and substituted by carboxyor ethoxycarbonyl; and

(X) an ethenyl group substituted by a member s elected from the groupconsisting of carboxy, ethoxycarbonyl, ureidocarbonyl (e.g.,Z-2-(aminocarbonylamino)ethenyl)), acylsulfonamidophenyl(e.g.,2-[4-[(4-chlorophenyl)sulfonylaminocarbonyl]phenyl]ethenyl), and4-carboxyphenyl (e.g., E-2-(4-carboxyphenyl)ethenyl;

R⁴ selected as hydrogen;

R⁵ selected from the group consisting of:

(I) n-butyl;

(II)(q) ethyl substituted by aralkoxycarbonyl wherein the aralkoxycontains 7 carbons; and

(II)(z) butyl substituted by aralkyloxycarbonylamino wherein the aralkylgroup contains 7 carbons;

A is as defined above; and

n=1.

The following provisos apply to the compounds of this invention:

(1) alkyls may be straight or branched chain;

(2) no carbon of an alkyl may be directly bonded to two heteroatoms;

(3) no heteroatom may be directly bonded to a sulfur, nitrogen oroxygen; and

(4) alkenyls of IX and X for R³ may not be 1,1-disubstituted, and acarbon of a double bond may not be directly bonded to an oxygen ornitrogen.

The salts of the compounds of formulae Ia, Ib and Ic includepharmaceutically-acceptable base- or acid-addition salts such as thosemade with a mineral acid, e.g., hydrochloric, or an organic acid such ascitric, maleic, fumaric or acetic. Base-addition salts include thosemade with alkali metal hydroxides such as sodium hydroxide, alkali metalcarbonates and bicarbonates, alkaline earth hydroxides and organic aminesalts. Such salts may be prepared by dissolving the peptide derivativein a mixture of water and a water-miscible organic solvent, adding anaqueous solution of the base and recovering the salt from the aqueoussolution.

The preferred compounds of the present invention are of the Sconfiguration (i.e., that of the naturally occurring L-amino acids) atchiral centers identified by * in formulae IIa, IIb, and IIc below. Themethods of synthesis described below in Methods A and B provide adiastereomeric mixture as a result of the presence of the products withboth the R and the S configurations at the chiral center identified bythe symbol Δ. The methods of separation and synthesis described below inMethods C and D provide compounds which are substantiallyenantiomerically and diastereomerically pure. The preferred compoundsare those assigned the S configuration at the center identified by thesymbol Δ.

As will be appreciated by those skilled in the art, the activity of theindividual isomers is not the same and, it is therefore preferred toutilize the more active isomer. The present invention includes both thediastereomeric mixture and the active S and R isomers.

As will be appreciated by those skilled in the art, the trifluoromethylketones can exist as solvates, particularly hydrates, represented byformulae IIIa, IIIb and IIIc, and these are encompassed by the presentinvention.

It is preferred to prepare the peptide derivatives of the presentinvention from commercially available alpha amino acids (i.e., those inwhich the NH₂ group is attached to the carbon atom next to the --COOHgroup). Because of this the preferred R² and R⁵ substitutents in theabove formulae for tri- and tetrapeptide derivatives are those obtainedfrom one of the following amino acids: alanine, valine, norvaline,leucine, isoleucine, norleucine, phenylalanine, tryptophan, tyrosine,asparagine, glutamine, aspartic acid, glutamic acid, lysine, threonine,serine, α-aminobutyric acid, and phenylglycine.

Preferred groups of compounds include those listed as the main title foreach of Examples 6, 11, 15-18, 20-28, 51-56, 58, 59, 62, 63, 65, 68, 71,72, 74, 75, 77-79, 82, 84-91, 93-111, 114, 115, 117, 119 and 121-126. Ofthese the ones for Examples 16, 24, 27, 52, 58, 71, 74, 77-79, 85, 89,93-96, 98, 100, 104-107, 110, 114, 115, 119 and 123-125 are morepreferred and those of Examples 77, 95, 104, 114 and 115 are the mostpreferred.

According to a further feature of the invention there are providedpharmaceutical compositions comprising a pharmaceutically-effectiveamount of at le ast one peptide derivative of formulae Ia, Ib or Ic anda pharmaceutically-acceptable diluent or carrier.

The compounds of formulae Ia, Ib and Ic can be prepared as follows:

Method A

Stage 1 is the preparation of the aminoalcohol of formula V(conveniently isolated as the hydrochloride salt). Henry condensation(McBee, E. T., et al, J. Amer. Chem. Soc., 78:4053 (1956))of anappropriate nitroalkane of formula R¹ CH₂ NO₂ (prepared by standardmethods if not otherwise available) with trifluoroacetaldehyde ethylhemiacetal of formula [CF₃ CH(OH)OCH₂ CH₃ ] provides a nitroalcohol offormula VI which is obtained as a mixture of two racemic diastereomers([2(RS),3(RS)] and [2(RS),3(SR)]). (For example, see Example 1b.)Reduction of the nitro group in a compound of formula VI with anappropriate reducing agent affords a compound of formula V as a mixtureof two racemic diastereomers ([2(RS),3(RS)] and [2(RS),3(SR)]). (Forexample, see Example 1c.) This amine salt is used directly for furthersynthesis.

Stage 2 is the conversion of a compound of formula V into keyintermediates of formulae IVa, and IVb and IVc using methods commonlyknown to those skilled in the art, such as those described in M.Bodanszky, Principles of Peptide Synthesis, Springer-Verlag, Berlin,(1984), and The Peptides. Analysis, Synthesis and Biology (ed. E. Grossand J. Meienhofer), Vols. 1-5, (Academic Press, New York) 1979-1983. Useof appropriately N-protected cyclic amino acids (such as CBZ-proline),followed by peptide coupling procedures and appropriate aminodeprotection affords compounds of formula IVa. Similar coupling withappropriate N-protected dipeptide acids and tripeptide acids anddeprotection affords compounds of formulae IVb and IVc, respectively. Inaddition, compounds of formula IVa can be converted into compounds offormulae IVb or IVc by utilizing the same peptide methodology. Theproducts obtained as here described are mixtures ([2(RS), 3(RS)] and[2(RS),3(SR)]) unless a separation is carried out.

Stage 3 is the conversion of intermediates of formulae IVa, IVb, or IVcinto intermediates of formulae VIIa, VIIb or VIIc by their reaction withappropriate reagents for the formation of amides, ureas, urethanes, andsulfonamides including acid chlorides, anhydrides, mixed anhydrides,isocyanates, carbonates such as 4-nitrophenyl carbonates (prepared asdescribed in Kunz, H. et al., Agew. Chem. Int. Ed. (Eng), 22, 783-784(1983), chloroformates, sulfonyl chlorides, and sulfinyl chlorides. Theproducts obtained as here described are mixtures ([2(RS),3(SR)] and[2(RS),3(RS)]) unless a separation is carried out.

As will be clear to one skilled in the art, the order of steps in Stage2 and 3 may be altered if appropriate considerations relative tocoupling methods, racemization, deprotection methods, etc. are followed.Thus, under appropriate conditions intermediates of formula VIIa mayalso be prepared directly from compounds of formula V; intermediates offormula VIIb may also be prepared directly from compounds of formulae Vor IVa; and intermediates of formula VIIc may also be prepared directlyfrom compounds of formulae V, IVa, or IVb.

Stage 4 is the oxidation of intermediates of formulae VIIa, VIIb or VIIcusing oxidation methods well known in the literature to provide productsof formulae Ia, Ib or Ic, respectively. Methods which are useful includethe use of oxalylchloride, DMSO and a tertiary amine (see Marx, M. etal., J. Org. Chem., 49,788-793 (1984) with the best results beingobtained with 10-20 equivalents of oxidizing agent), the use of aceticanhydride and DMSO, the use of chromium trioxide pyridine complex inmethylene chloride, and the use of Dess-Martin periodinane[1,1,1-triacetoxy-2,1-benzoxiodol-3(3H)-one] (method of Dess, D. B. etal, J. Org. Chem., 48, 4155-56 (1983)). The preferred method is the useof Dess-Martin periodinane. Unless they have been separated, theproducts Ia, Ib and Ic obtained by this method will contain a mixture[3(RS)] which will consist substantially of two diastereomers if thecenters corresponding to those indicated with an * in formulae IIa, IIb,and IIc, respectively, are substantially enantiomerically pure.

Stage 5 is the conversion of products of formulae Ia, Ib or Ic intoother products of formulae Ia, Ib or Ic and includes saponification,coupling, and deprotecting reactions. The stereochemistry of the productmixture is the same as that of Stage 4.

As will be clear to one skilled in the art, alternative sequences ofsteps to products of formulae Ia, Ib or Ic may be followed ifappropriate considerations relative to coupling methods, racemization,deprotection methods, etc. are followed. For example, in analogy toStage 3, intermediates of formulae IVa, IVb or IVc may be converted intocompounds corresponding to intermediates of formulae VIIa, VIIb or VIIcbut in which the portion corresponding to formula A is protected or notfully elaborated. Deprotection or final elaboration of the portioncorresponding to formula A may then be carried out before the oxidationstep to provide intermediates of formulae VIIa, VIIb or VIIc.Alternatively, an oxidation step corresponding to Stage 4 may be carriedout and the portion corresponding to formula A of the resultingtrifluormethyl ketones may be deprotected or elaborated (analogously toStep 5) to provide corresponding products of formula Ia, Ib or Ic.

Method B is a preferred method relative to Method A

Stage 1 involves separation of the mixture of racemic diastereomers offormula VI obtained as the product of Method A, Stage 1, by fractionaldistillation and crystallization to obtain a nitro alcohol of formula VIas a substantially pure racemic diastereomer [2(RS),3(SR)] substantiallyfree of the other racemic diastereomer [2(RS),3(RS)]. Reduction of thenitro group by the preferred method of hydrogenation over a 10%palladium on carbon catalyst provides a compound of formula V as oneracemic diastereomer [2(RS),3(SR)] substantially free of the otherracemic diastereomer. (It will be appreciated by one skilled in the artthat, alternatively, the diastereomer [2(RS),3(RS)] may also be used forthe production of compounds of this invention.)

Stage 2 is the same as in Method A but uses the amine of formula Vprepared as described in Method B, Stage 1. The products obtained bythis method are substantially pure [2(RS),3(SR)] mixtures.

Stage 3 is the same as in Method A but uses the product preparedaccording to Method B, Stage 2. The products obtained by this method aresubstantially pure [2(RS),3(SR)] mixtures.

As in Method A, the order of steps in Stage 2 and Stage 3 may be alteredunder appropriate conditions.

Stage 4 is the same as Stage 4 of Method A. The product mixture obtainedis the same as the product mixture obtained in Method A, Stage 4.

Stage 5 is the same as that of Method A, Stage 5.

Method C is a method for direct synthesis of individual ("resolved")isomers of formulae Ia, Ib, and Ic which are substantially free of theother diastereomers, for example, for products corresponding to IIa,IIb, and IIc in which the centers corresponding to * and a are all S

Stage 1 involves resolution of the racemate of formula V preparedaccording to Method B, Stage 1. After the free base corresponding to Vis liberated, resolution is carried out by formation of thediastereomeric salts with D-tartaric acid and separation of those saltsby fractional crystallization. The desired amine is then obtained fromthe separated salts by freeing the base to afford, for example, the freebase corresponding to 2(R)3(S) in a compound of formula V. The productthus obtained is substantially enantiomerically and diasteriomericallypure.

Stages 2 and 3 are substantially the same as Stages 2 and 3 in Methods Aand B, but limited to methods which will avoid racemization of centerswhich correspond to those marked * in formulae IIa, IIb, and IIc. Theproducts thus obtained are essentially enantiomerically anddiastereomerically pure.

Stage 4 is limited to methods which will avoid racemization at thecenters labelled * and Δ in formulae IIa, IIb and IIc. The preferredmethod is the use of Dess-Martin periodinane. The products Ia, Ib and Icthus obtained are essentially enantiomerically and diastereomericallypure.

Stage 5 is limited to methods which will avoid racemization at thecenters labelled * and Δ in formulae IIa, IIb and IIc.

Method D

Stage 1 is a separation of compounds of formulae Ia, Ib or Ic preparedby Methods A or B which are diastereomeric mixtures (owing to the 3(RS)center) into their single isomers which are substantiallydiastereomerically and enantiomerically pure. The preferred method forcompleting this separation is the use of preparative chromatography,e.g. medium pressure liquid chromotography (MPLC) and high pressureliquid chromatography (HPLC).

Stage 2 is the same as Stage 5, Method C.

Inhibition Measurements

The potency of compounds of the invention to act as elastase inhibitorswas initially determined by the ability of a compound of the inventionto inhibit the action of human leukocyte elastase (HLE) on a lowmolecular weight peptide substrate. The potency of an inhibitor isevaluated by obtaining a kinetic determination of the dissociationconstant, K_(i), of the complex formed from the interaction of theinhibitor with HLE. The substrate used was the anilidemethoxysuccinyl-alanyl-alanyl-prolyl-valine-p-nitroanilide as describedby Ko Nakajima et al. in the J. Biol. Chem., 254:4027-4032 (1979) and byT. Teshima et al. in J. Biol. Chem., 257:No. 9, 5085-5091 (1982). TheHLE enzyme used in these studies may be obtained from Elastin Productsof St. Louis, Missouri or can be purified according to B. R. Viscarelloet al. in Preparative Biochemistry, Vol. 13, pages 57-67, (1983) asfollows, all work having been done in a cold room at 4° C.

Salt Extraction-DNase Treatment: The starting material, 193 g ofpurulent sputum, was homogenized with 200 ml of cold distilled water andcentrifuged at 30,000×gravity for 20 min. at 4° C. The supernatant wasdiscarded and the pellet extracted with high salt and treated with DNaseas per the method of D. Y. Twumasi et al. in J. Biol. Chem., 252:1917-1926 (1977). Chromatography on Elastin Agarose: The precipitatefrom the DNase digest was taken up in two 40 ml portions of 50 mM Tris,1.0 M NaCl, pH 8; the suspension was centrifuged and the resultingsupernatant applied directly to a column of soluble elastin-Sepharose 4B(2.5×20 cm). The column was washed with equilibrating buffer (50 mMTris, 50 mM NaCl, pH8.0) until the optical density at 280 nm (OD₂₈₀) ofthe eluate returned to baseline. Additional contaminating protein waseluted with two column volumes of 50 mM acetate, 1.0 M NaCl, pH 5.0.Elastase and cathepsin G (HLC-G) were finally eluted with 50 mM acetate,1.0 M NaCl, 20% DMSO, pH 5.0. The column was developed at 6 ml/min withthe collection of 10 ml fractions. The active fractions were pooled,dialyzed vs. two 6 liter changes of 50 mM acetate, 0.1 M NaCl, pH 5.5,and concentrated to 40 ml on an Amicon® ultrafiltration unit (YM-10membrane). CM-Chromatography: The concentrated active fraction wasapplied to a column of CM-Sephadex® C-50 (2.2×10 cm) previouslyequilibrated with 50 mM acetate, 0.1M NaCl, pH 5.5 and the column wasthen washed with this buffer to remove contaminating protein. Elutionwas continued with 50 mM acetate, 0.2M NaCl, pH 5.5 and resulted in thedisplacement of a peak of activity assayed againstBz--Phe--Val--Arg--pNA. HLE was next eluted with the acetate buffercontaining 0.45M NaCl, while elution of HLC--G required the presence of1.0M NaCl in the buffer as described by R. Martodam et al. inPreparative Biochemistry, Vol. 9, pages 15-31 (1979). This column wasdeveloped at 30 ml/hr with the collection of 5.5 ml fractions. From thethus purified HLE, a standard rate of production of p-nitroaniline wasmeasured at 25° C spectrophotometrically in the visible spectrum at 410nanometers with automatic data acquisition from a Cary 210spectrophotometer obtained from Varian Associates. Reactions wereinitiated by injection of 10 microliters of the HLE solution into a 3milliliter cuvette containing 2.89 milliliters of buffer (10 millimolarsodium phosphate, 500 millimolar NaCl, pH 7.6), 50 microliters substratesolution in DMSO, and 50 microliters of DMSO. Initial, steady-statereaction velocities of p-nitroaniline production were calculated by afit of the experimental data to a linear dependence on time by linearleast squares. This velocity, determined with no inhibitor present, wasused as a standard in the calculation of inhibitor K_(i) values.

In general, the peptide derivatives of the present invention were foundto be "slowbinding" inhibitors of HLE and therefore required specialmethods of analysis to accurately determine K_(i) values for theirinhibition of HLE (see Williams, J. W. and Morrison, J. F., Meth. Enz.63, 437 (1979) for a description of these methods.) In a typicalexperiment, 2.89 ml of buffer (10 millimolar sodium phosphate, 500millimolar sodium chloride, pH 7.6), 50 microliters of inhibitorsolution in DMSO, and 50 microliters of substrate solution in DMSO wereadded to a 3 milliliter cuvette. The cuvette was stoppered, invertedseveral times to mix its contents and maintained at (25° C.) in thespectrophotometer. After a period of five minutes to allow the reactionsolution to come to thermal equilibrium, 10 microliters of stock enzymesolution were added to the cuvette to initiate the reaction. Duplicateor triplicate runs were done at zero inhibitor concentration and atleast three non-zero inhibitor concentrations. K_(i) values werecalculated according to methods outlined in the above reference byWilliams and Morrison. The K_(i) values for selected compounds were lessthan 10⁻⁷ M.

Animal Models

Animal models of emphysema include intratracheal (i.t.) administrationof an elastolytic protease to cause a slowly progressive, destructivelesion of the lung. These lesions are normally evaluated a few weeks toa few months after the initial insult. However, these proteases alsoinduce a lesion that is evident in the first few hours. The early lesionis first hemorrhagic, progresses to an inflammatory lesion by the end ofthe first 24 hours and resolves in the first week post insult. To takeadvantage of this early lesion, the following model was used.

Hamsters are first lightly anesthetized with Brevital. Phosphatebuffered saline (PBS) pH 7.4, either alone or containing 400 ξg of humanleukocyte elastase (HLE), is then administered directly into thetrachea. Twenty-four hours later the animals are killed and the lungsremoved and carefully trimmed of extraneous tissue. Followingdetermination of wet lung weight, the lungs are lavaged with PBS andtotal lavagable red and white cells recovered are determined. The valuesfor wet lung weights, total lavagable red cells and total lavagablewhite cells are elevated in a dose-dependent manner followingadministration of HLE. Compounds that are effective elastase inhibitorscan prevent or diminish the severity of the enzyme-induced lesionresulting in lower wet lung weight and reduced values for totallavagable cells, both red and white, relative to administration of HLEalone. Compounds can be evaluated by administering them either with orat various times prior to administration of HLE to determine theirutility in preventing an HLE lesion. Compounds of this inventionproduced statistically significant reductions in wet lung weight andtotal lavagable cells relative to HLE alone. Compounds of the presentinvention exhibited activity in at least one of the tests describedabove under Inhibition Measurement or Animal Model. It should be notedthat there was not always a direct correlation between the activities ofthe compounds measured as K_(i) values in the Inhibition Measurementtest and the reduced values for total lavagable cells and wet lungweights relative to the administration of HLE alone obtained in theAnimal Model test. It is thought that the Animal Model test is morepredictive of the activity of such compounds in the treatment ofemphysema.

Pharmacokinetics: Male Syrian hamsters (80 to 120 g) are injectedintravenously with the test compound. Prior to injection and at varyingtime periods thereafter, they are lightly anesthetized with ether andblood samples of approximately 0.2 ml each are withdrawn by cardiacpuncture. The blood is expressed into 2 ml centrifuge tubes and allowedto clot for one hour. The sample is then centrifuged and the serumremoved.

Drug levels are determined by first inactivating endogenous elastaseinhibitors by incubation of 50 microliters of serum with an equal volumeof buffer containing 5 mg/ml bovine pancreatic trypsin for 5 min. Thetrypsin inactivated serum (10 microliters) is then added to a 0.52 mlcuvette containing buffer made 20 nM with respect to HLE. After anadditional 30 min. incubation, the reaction is started by the additionof substrate (350 microliters) (MeOSuc--Ala--Ala--Pro--Val--pNA, 1.6 mm)and the reaction monitored spectrophotometrically at a wavelength of 410nM. For comparative purposes, serum persistence of the test compounds isdetermined in the following manner:

Percent inhibition of serum samples is calculated as follows: ##EQU1##where Vo is the velocity obtained in the presence of control serum andVi is the velocity of the inhibited reaction. Data are expressed as logpercent inhibition vs. time post inhibitor administration. Anapproximate serum half-life (t1/2) is calculated from the resultantcurve.

The compounds of the present invention may be administered to awarm-blooded animal in need thereof, particularly a human, for thetreatment of conditions of pulmonary emphysema, atherosclerosis,rheumatoid arthritis, and osteo arthritis, in particular for emphysema.The mode of administration may be oral, parenteral, including thesubcutaneous deposit by means of an osmotic pump, or via a powdered orliquid aerosol. These may be conventionally formulated in an oral orparenteral dosage form by compounding about 10 to 250 mg per unit ofdosage with conventional vehicle, excipient, binder, preservative,stabilizer, flavor or the like as called for by accepted pharmaceuticalpractice e.g. as described in U.S. Pat. No. 3,755,340. For parenteraladministration, a 1 to 10 ml intravenous, intramusular or subcutaneousinjection would be given containing about 0.02 to 10 mg/kg of bodyweight of a compound of the invention 3 or 4 times daily. The injectionwould contain a compound of the invention in an aqueous isotonic sterilesolution or suspension optionally with a preservative such as phenol ora solubilizing agent such as ethylenediaminetetraacetic acid (EDTA). Ina powdered aerosol, compounds of the invention may be administered inthe same manner as cromolyn sodium via a Spinhaler® turbo-inhaler deviceobtained from Fisons Corp. of Bedford, Mass. at a rate of about 0.1 to50 mg per capsule, 1 to 8 capsules being administered daily for anaverage human. Each capsule to be used in the Spinhaler® contains therequired amount of a compound of the invention with the remainder of the20 mg capsule being a pharmaceutically-acceptable carrier such aslactose. In a liquid aerosol, the compounds of the invention areadministered at the rate of about 100 to 1000 micrograms per "puff" oractivated release of a standard volume of propellant. The liquid aerosolwould be given at the rate of 1 to 8 puffs per day with variation indosages due to the severity of the condition being treated, the weightof the patient and the particle size distribution of the aerosol sincesmaller particles will achieve greater lung penetration. Propellants,e.g., a fluorinated hydrocarbon or isobutane, containers, valves andactuators for liquid aerosols are described by L. Lachman et al. in "TheTheory and Practice of Industrial Pharmacy" , Lea and Febiger,Philadelphia (1976).

In the following Examples and throughout the specification, thefollowing abbreviations and conventions are used: atm (atmospheres); bp(boiling point); °C. (degrees Celsius) with all temperatures being in°C. unless otherwise noted; g (grams); hr (hours); mg (milligrams); min(minutes); ml (milliliters); l (liters); mol (moles); mmol (millimoles);mp (melting point); bp (boiling point); N (normal); nm (nanometers); nM(nanomolar); satd or sat'd (saturated); aq (aqueous); conc(concentrated); ×(times); room temperature (20°-23°); DCC(1,3-dicyclohexylcarbodiimide); DMF (dimethylformamide); DMSO (dimethylsulfoxide); Et₂ O (diethyl ether); EtOAc (ethyl acetate); HOAc (aceticacid); HOBT (1-hydroxybenzotriazole); MeOH (methyl alcohol); EtOH (ethylalcohol ); Pd/C (palladium on charcoal catalyst ); pNA(paranitroanilide); THF (tetrahydrofuran); CBZ (benzyloxycarbonyl);t-BOC (tertiarybutyloxycarbonyl); DMF (dimethylformamide); TEA(triethylamine); DCC (1,3-dicyclohexylcarbodiimide); AcOH (acetic acid);S.M. (starting material); NMM (N-methylmorpholine); ≦ (less than orequal to); TEA (triethylamine); TFA (trifluoroacetic acid); Ac₂ O(acetic anhydride); CDI (carbonyldiimidazole); WSCDI (water solublecarbodiimide:1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride);DMAP (4-dimethylaminopyridine); Dess-Martin periodinane(1,1,1-triacetoxy-2,1-benzoxiodol-3(3H)-one); HCl gas (gaseousHCl)--otherwise, HCl is an aqueous solution; Rh/C (rhodium on charcoalcatalyst); φ (phenyl group); TLC (thin layer chromatography on silicagel unless otherwise specified); R_(f) (relative mobility in TLC); MPLC(medium pressure liquid chromatography); HPLC (high pressure liquidchromatography), t_(R) (HPLC retention time in min), FR (HPLC flow ratein ml/min); Col A (Zorbax® ODS analytical column, 4.6 mm×25 cm); Col B(Phenomenex® Zorbax® C.-8 analytical column, 4.6 mm×35 cm); Col C (AltexUltrasphere®/Octyl 10 mm I.D.×25 cm 5 micron analytical and preparativecolumn); flash chromatography (flash column chromatography on silica gelunless otherwise specified); suction chromatography (suction columnchromatography on silica gel). In addition, C, H, N, etc. (theconventional symbols for the elements) are used; 133.3 Pascals=1 Torr asa conversion factor with 760 Torr =14.7 pounds per square inch (psi); ¹H NMR (nuclear magnetic resonance) spectra were obtained using either a80 MHz or 250 MHz instrument and tetramethylsilane (TMS) as an internalstandard (the solvent for the particular example is noted in theexample), δ (parts per million downfield from TMS); with s (singlet); d(doublet); dd (doublet of doublets); m (multiplet). Nomenclature: Foruniformity and clarity, "amino acid sequence type" names are usedwhenever possible. In addition, amines of formula V, nitro compounds offormula VI, and the N-substituents of C-terminal amides of formulae I,II, III, IV, and VII which are formally derived from V are numbered asshown in formula V, VI and the partial formulae set out following them.

When needed or as noted, various examples were repeated if more materialwas required.

EXPLOSION WARNING: The nitro alcohols of formula VI and theirnitroalkane precursors are potentially explosive. The compound offormula VI, R¹ ═CH(CH₃)₂ (Examples 1b and 4b) is thermally unstable andon a small scale, has been observed to decompose with considerableviolence in the range 170°-180° C. Samples of the material have beensafely distilled at reduced pressure (95°-105° C./2.0 torr).Recommendtions for safe distillation include keeping the oil bath below110° C., never taking still residues below 15% of the orginal crudevolume, and conducting the distillation behind a safety screen. ##STR4##

EXAMPLE 1 2 (RS),3(SR)-3-Amino-4-methyl-1,1,1-trifluoro-2-pentanolhydrochloride salt a. 2-Methyl-1-nitropropane

1-Iodo-2-methylpropane (94.0 g, 0.51 mol) was added dropwise to apre-cooled (0° C.) suspension of AgNO₂ (100.0 g, 0.65 mol) in Et₂ O (180ml). The reaction was protected from light and stirred overnight as itwas allowed to warm to room temperature. The reaction mixture wasfiltered through Celite®. The filtrate was concentrated under vacuum andthe residue was distilled under vacuum (caution: potentially explosive)to give the product (37.7 g, 0.366 mol); b.p. 61°-65° C. at 6913.6Pascals (52 mm Hg).

b. 2(RS),3(SR)-4-Methyl-3-nitro-1,1,1-trifluoro-2-pentanol

See EXPLOSION WARNING

1-Nitro-2-methylpropane (37.7 g, 0.366 mol) from Example 1a,trifluoroacetaldehyde ethyl hemiacetal (58.5 g, 0.366 mol, 90% purity)and K₂ CO₃ (3.4 g, 0.025 mol) were mixed and stirred at 60° C. for 3 hr.and then at room temperature for 3 days. Brine (75 ml) and 1N aqueousHCl (50 ml) were added and the lower organic layer separated. Theaqueous layer was extracted with Et₂ O (twice with 250 ml each) and thecombined organic layers were washed with brine, dried over Na₂ SO₄,filtered and concentrated under vacuum. The residue was purified byflash chromatography on silica gel with a gradient elution of CH₂ Cl₂:hexane (50:50), CH₂ Cl₂ :hexane (75:25), CH₂ Cl₂ (100%) and MeOH:CH₂Cl₂ (5:95) to give the product (44.9 g); TLC, R_(f) =0.65, silica gel,EtOAc: CHCl₃ (5:95).

c. 2(RS),3(SR)-3-Amino-4-methyl-1,1,1-trifluoro-2-pentanol hydrochloridesalt

A solution of a portion of the product of Example 1b (37.0 g, 0.184 mol)in Et₂ O (200 ml) was added dropwise to a suspension of lithium aluminumhydride (22.0 g, 0.58 mol) in Et₂ O (800 ml). The reaction mixture wasstirred for 45 min. and a saturated aqueous solution of Na₂ SO₄ (110 ml)was carefully added. The resulting suspension was filtered; the filtratewas treated with ethereal HCl and concentrated under vacuum to give theproduct (37.6 g) which was used without further purification. ¹ H NMRdata (CD₃ COCD₃)(250 MHz): 1.2δ, m, 6H; 2.3δm, 1H; 3.58δ, m, 1H; 4.98δ,m, 2H; 7.78δ, m, (NH2).

EXAMPLE 22(RS),3(SR)-N-[3-(4-Methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamidea. 2 (RS),3(SR)-1-[(Phenylmethoxy)carbonyl]-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

A solution of isobutyl chloroformate (11.01 g, 0.08 mol) in dry THF (30ml) was added dropwise over 5 min to a pre-cooled solution (-15° C.) ofCBZ-L-proline (19.21 g, 0.077 mol) and N-methylmorpholine (8.18 g, 0.081mol) in THF (300 ml) under a nitrogen atmosphere. The reaction mixturewas stirred at -15° C. for 15 min. The reaction temperature was thenreduced to -40° C. and a solution of a portion of the product of Example1c (16.00 g, 0.077 mol) and N-methylmorpholine (8.18 g, 0.081 mol) inTHF (200 ml) was added dropwise to the reaction. The reaction mixturewas stirred at -40° C. for 1 hr. and then allowed gradually to warm toroom temperature and stirred for an additional hour. The reaction wasfiltered and concentrated under vacuum. The resulting syrup wasdissolved in CHCl₃, and washed with aqueous 20% citric acid (twice with75 ml each). The organic layer was concentrated under vacuum to give thecrude product as a white cloudy syrup. The crude product was trituratedwith ether: hexane (1:2) to give 3 crops of the product as a whitepowder (17.11 g); TLC, R_(f) =0.47, silica gel, MeOH:CHCl₃ (3:97); m.p.,152°-154° C.; HPLC, t_(R) =14.06, 16.63, 18.23, 19.00, Zorbax® ODSanalytical column, H₂ O:CH₃ CN (70:30), flow rate=3 ml/min.

b.2(RS),3(SR)-N-[3-(4-Methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

The product of Example 2a (2.00 g, 4.97 mmol) was dissolved in absoluteethanol (50 ml), 10% Pd/C (0.5 g) was added and the reaction mixture washydrogenolyzed (310126.53 Pascals, 45 psi hydrogen) for 3 hr. at roomtemperature. The reaction mixture was filtered through Celite® and thesolvent was removed under vacuum to give the product (1.36 g) which wasused without further purification.

EXAMPLE 32(RS),3(SR)-L-Valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamidea. N-[(Phenylmethoxy)carbonyl]-L-valyl-L-proline methyl ester

1-Hydroxybenzotriazole (163.3 g, 1.2 mol) was added to a pre-cooled (0°C.) solution of N-benzyloxycarbonyl-L-valine (151.8 g, 0.6 mol) in DMF(1.3 liter) and stirred for 15 min. A suspension of L-proline methylester hydrochloride (100.0 g, 0.6 mol) and TEA (64.2 g, 0.63 mol) in DMF(0.7 liter) was added, followed by DCC (137.1 g, 0.66 mol). The reactionmixture was stirred for 3 hr. at 0° C. and then at room temperature for3 days. The reaction mixture was filtered and the filtrate concentratedunder vacuum. The residue was mixed with EtOAc (0.75 liter) andfiltered. The filtrate was washed successively with 20% aqueous citricacid (0.75 liter), saturated aqueous NaHCO₃, and brine. The organicphase was dried over MgSO₄, filtered and concentrated under vacuum togive the crude product (271.3 g). The product was purified by flashchromatography on silica gel using a gradient elution starting with CH₂Cl₂ and finishing with MeOH:CH₂ Cl₂ (4:96) to give the product (218.1g); TLC, R_(f) =0.48, silica gel, MeOH:CHCl₃ (5:95).

b. N-[(Phenylmethoxy)carbonyl]-L-valyl-L-proline

To a solution of a portion of the product of Example 3a (158.8 g, 0.438mol) in MeOH (1.6 liter) was added 1N aqueous NaOH (500 ml) and thesolution stirred at room temperature for 17 hr. 1N aqueous NaOH (100 ml)was added and stirring continued for 5 hr. Additional 1N aqueous NaOH(50 ml) was added and the reaction was stirred overnight. The reactionwas concentrated under vacuum to remove the MeOH. H₂ O (1.0 liter) wasadded and the aqueous solution extracted with Et₂ O. The aqueoussolution was acidified with 1N aqueous HCl (700 ml) and extracted withEtOAc. The EtOAc extracts were washed with brine, dried over Na₂ SO₄,filtered and concentrated under vacuum to give the product (159.2 g);TLC, R_(f) =0.34, silica gel, MeOH:CHCl₃ : AcOH (5:94:1).

c.2(RS),3(SR)-[(Phenylmethoxy)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

Isobutylchloroformate (77.3 g, 0.566 mol) was added to a pre-cooled(-15° C.) solution of N-methylmorpholine (59.25 g, 0.566 mol) and theproduct of Example 3b (197.2 g, 0.566 mol) in dry THF (2.5 liters) andthe reaction stirred for 10 min. The temperature was reduced to -40° C.and N-methylmorpholine (59.25 g, 0.566 mol) was added, followed by thedropwise addition of a solution of the product of Example 1c (117.5 g,0.566 mol) in THF (2.5 liter). The reaction was allowed to warm to roomtemperature and stirred for three days. The reaction mixture wasfiltered and the filtrate concentrated under vacuum. The residue wasdissolved in EtOAc and washed successively with H₂ O, 1N aqueous HCl andbrine. The organic layer was dried over Na₂ SO₄, filtered andconcentrated to give the crude product (267.8 g). The product waspurified by flash chromatography on silica gel using a gradient elutionof THF:toluene (5:95) to THF:toluene (25:75) to give the product (183.8g); TLC, R_(f) =0.4, silica gel, THF:toluene (20:80).

d.2(RS),3(SR)-L-Valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

A mixture of a portion of the product of Example 3c (36.7 g, 0.073 mol)and 10% Pd/C (10%, 50% water wet) in EtOH (0.6 liter) was hydrogenatedon a Parr shaker (303,924 Pascals, 3 atm H₂). After 1 hr. the reactionvessel was evacuated and re-pressurized with H₂. After an additional 0.5hr. the reaction mixture was filtered through Celite® and concentratedunder vacuum to give the product (26.0 g); TLC, R_(f) =0.16, silica gel,MeOH:CHCl₃ (5:95).

EXAMPLE 4 2 (RS),3(SR)-3-Amino-4-methyl-1,1,1-trifluoro-2-pentanolhydrochloride salt a. 2-Methyl-1-nitropropane

An alternative method for making the compound of Example 1a is asfollows.

A 5-liter, 3-necked, round-bottomed flask was equipped with a mechanicalstirrer, thermometer, addition funnel and N₂ inlet. The flask wascharged with AgNO₂ (1006.8, 6.54 mol) in Et₂ O (2.5 liter), and isobutyliodide (927.2 g, 5.03 mol) was placed in the addition funnel. Both theflask and the addition funnel were wrapped in aluminum foil to protectthe reaction from light. After the stirred suspension was cooled toapproximately 5° C. (ice bath), dropwise addition of the iodide over a 2hr period was begun. The reaction temperature was maintained at or lessthan 5° C. throughout the course of the addition. When the addition wascomplete, the reaction vessel was packed in ice and allowed to warmslowly to room temperature overnight. NMR analysis of an aliquot takenfrom the reaction mixture after 48 hr of stirring demonstrated that allof the isobutyl iodide had been consumed. The reaction mixture wasfiltered through Celite® to remove silver salts and the filter cake waswashed with Et₂ O (3×500 ml). The combined filtrates were dried MgSO₄,filtered and concentrated on a rotary evaporator (bath temp=35° C.) toabout 600 ml. Fractional distillation (atmospheric pressure) (caution:potentially explosive) gave the purified nitro compound (350.4 g, 68%yield); b.p. 135°-142° C.

b. 2(RS),3(SR)-4-Methyl-3-nitro-1,1,1-trifluoro-2-pentanol

See EXPLOSION WARNING

A 3-liter, 3-necked, round-bottomed flask equipped with a mechanicalstirrer and N₂ inlet was charged with K₂ CO₃ (470.0 g, 3.4 mol), theproduct of Example 4a (350.0 g, 3.4 mol) and finallytrifluoroacetaldehyde ethyl hemiacetal (708.0 g, 4.4 mol). The mixturewas vigorously stirred at room temperature for 76 hr, at which time ¹H-NMR demonstrated the nearly complete consumption of the nitroalkane.The reaction mixture was diluted with CH₂ Cl₂ and filtered. The filtratewas treated with aqueous HCl until pH=3. The layers were separated andthe aqueous layer was washed with CH₂ Cl₂ (500 ml). The combined CH₂ Cl₂portions were washed with H₂ O (1 liter) and brine (1 liter). Drying(MgSO₄) and concentration gave 854.6 g of crude product as a yellow oil.¹ H-NMR showed the two diastereomeric nitro alcohols (present in theratio of about 3:1 as quantified by integration of the alcohol protons)which consistently appear in the range δ6.0-6.5 when run in acetone-d₆contaminated by solvents and small amounts of starting materials.

Distillation at reduced pressure gave the following fractions:

    ______________________________________                                        Wt.       BP (°C.)                                                     ______________________________________                                        A   191.7 g   42°-50° C./atm.                                                                  S.M. + solvents                                B    34.8 g   35°/1 torr-45°/.5 torr                            C   213.6 g   45°/.5 torr-95°/1.5 torr                          D   337.8 g   95°/1.5 torr-105°/2 torr                          E   114.0 g   trap volatiles                                                  ______________________________________                                    

To simplify purifications in subsequent synthetic steps, an effort wasmade at this point to obtain the major diastereomeric pair in asubstantially pure state and to advance only this material through thesequence. The major diastereomeric pair crystallizes from the mixture ofdiastereomers, as well as from cold pentane, to yield colorless needles.Thus, fraction C from the above distillation was allowed to crystallizeovernight in a refrigerator. The product was collected, washed with coldpentane and dried for several hours in a vacuum oven (Caution! Thismaterial is somewhat volatile and significant quantities can be lostunder extended vacuum treatment) to give 52.0 g of substantially purematerial. The fractions known (by NMR) to contain significant quantitiesof the desired isomer were repetitively treated in this fashion (andredistilled to provide new fractions further enriched in the desireddiastereomer) to eventually obtain a total of 197.7 g of substantiallypure nitro alcohol. This amount represents the type of work done, but itdoes not reflect the upper limit of the yield.

c. 2(RS),3(SR)-3-Amino-4-methyl-1,1,1-trifluoro-2-pentanol hydrochloridesalt

Anhydrous EtOH (232 ml) was added to 10% Pd/C catalyst (2.30 g) under N₂*. The product of Example 4b (22.93 g, 0.144 mol) was added and theresultant mixture was placed on a Parr hydrogenation apparatus (about480,000 Pascals, 55 psi H₂) overnight. Catalyst was removed byfiltration through Celite®. The filter cake was then washed with EtOH.HCl gas was bubbled through the combined filtrates until approximately 8g (about 0.22 mol) were absorbed. The solution was concentrated on arotary evaporator and the resultant residue was concentrated severaltimes from Et₂ O to obtain a white solid. The solid was washed with Et₂O and dried overnight in a vacuum oven to yield 20.79 g (88%) of aminehydrochloride. For the m.p., with slow heating the material softens at90° C. and melts at 118°-120° C. When a sample is plunged into a bathpreheated to 110° C., it melts instantaneously.

EXAMPLE 5(RS),3(SR)-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamidea. N-[(Phenylmethoxy)carbonyl]-L-valyl-L-proline methyl ester

A solution of CBZ-L-Valine (100.0 g, 0.40 mol) in DMF (1 liter, driedover sieves) was added to a 3-liter, 3-necked, round-bottomed flaskequipped with a mechanical stirrer, N₂ inlet and a thermometer. Thereaction was cooled to 0° C. and HOBT hydrate (108.1 g, 0.80 mol) wasadded. Approximately 15 min of stirring were allowed before adding a DMF(500 ml) slurry of L-proline methylester hydrochloride (66.2 g, 0.40mol) and TEA (41.8 g, 0.42 mol) in one portion. Additional DMF (500 ml)was used to complete the transfer of the slurry. DCC (90.8 g, 0.44 mol)was added to the reaction and was washed down with DMF (100 ml). Thereaction was stirred for 3 hr at 0° C. before allowing it to warm toroom temperature and stir for 3 days. The reaction mixture was thenfiltered and the filtrate concentrated at reduced pressure. The filtercake was washed with EtOAc (3×1 liter), and concentration of theresultant filtrate gave material that was combined with the residue fromconcentration of the DMF solution. The combined product mixture (about2.5 liters) was diluted with Et₂ O (2 liters) and stored in therefrigerator overnight. Precipitate was removed by filtration. When thefiltrate was washed with 1N HCl (1 liter), additional precipitate formedand was removed by filtration. The filtrate was then washed with 1N HCl(1 liter), H₂ O (0.5 liter), saturated NaHCO₃ (2×1 liter) and brine (0.5liter). Drying MgSO₄ and concentration gave 587.2 g of crude product.This material was flash chromatographed on silica gel (3.5 kg) withgradient elution (CH₂ Cl₂ to 5% MeOH:CH₂ Cl₂ (5:95). Mixed fractionswere subjected to repeated chromatography to remove impurities.Combination of the fractions containing the desired product gave 500.7 g(87%) of material contaminated with a small amount of low R_(f)impurity; TLC, R_(f) =0.37, silica gel, Et₂ O: hexane (3:1); R_(f)=0.53, silica gel, MeOH:CHCl₃ (5:95).

b. N-[(Phenylmethoxy)carbonyl]-L-valyl-L-proline

A methanolic (4 liters) solution of the product of Example 5a (500.7 g,1.38 mol) was added to a 12-liter, 3-necked, round-bottomed flaskequipped with a mechanical stirrer and an N₂ inlet. To the stirredsolution was added 1N NaOH (1.4 liters), bringing the pH toapproximately 13. After the reaction had stirred for 3 hr, the pHdropped to 11. Additional 1N NaOH (0.1 liter) was used to bring the pHto 12 and the reaction was stirred overnight at room temperature. MeOHwas removed from the reaction mixture by concentration on a rotaryevaporator. During the course of the solvent removal, a total of 1 literof H₂ O was added to reduce the concentration of the base. The aqueoussolution was washed with Et₂ O before acidifying with 1N HCl (1.5liters) to a pH of approximately 3.5. The layers were separated and theaqueous layer was extracted with EtOAc (3×1 liter). The combinedorganics were washed with brine (1 liter), dried (MgSO₄) andconcentrated to give 493.0 g (100%) of product as a white solid; TLC,R_(f) =0.51, silica gel, MeOH:CHCl₃ (5:95) with added AcOH.

c.2(RS),3(SR)-[(Phenylmethoxy)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

The product of Example 5b (105.3 g, 0.302 mol) was dissolved in dry THF(1.5 liters) under N₂ in a 3-liter, 3-necked, round-bottomed flaskequipped with a mechanical stirrer, thermometer, N₂ inlet and anaddition funnel. The solution was cooled to -35° C. and treated with 1equivalent (34 ml, 0.309 mol) of NMM. Isobutyl chloroformate (39 ml,0.307 mol) was added dropwise over 20 min while maintaining thetemperature ≦-35° C. After the addition was complete, the reaction wasstirred for 1 hr at -35° C. A second equivalent of NMM (34 ml) wasadded. The product of Example 4c (62.8 g, 0.302 mol) in THF (300 ml) wasthen added at such a rate that the temperature was maintained at ≦-35°C. After the addition was complete, the temperature was kept ≦-35° C.for 1 hr before the mixture was allowed to warm to room temperature withstirring overnight. The reaction mixture was filtered and the filtercake was washed with THF (1 liter). The combined filtrates wereconcentrated to give 189 g of crude product. This material was flashchromatographed on silica gel (5000 ml) and eluted with THF:toluene(1:9). Once product began to elute, the solvent polarity was altered ingradient fashion: THF:toluene (15:85); THF:toluene (20:80); and, finallyMeOH:THF:toluene (2.5:30:70) (MeOH use was minimized to prevent theelution of low R_(f) impurities). Concentration of the column fractionsfollowed by drying under vacuum overnight gave 12.0 g (8%) of slightlyimpure product and 131.6 g (87%) of substantially pure material. (NOTE:Solutions of this material when taken to complete dryness yielded a foamthat eventually solidified under extended vacuum treatment. Care hadbeen taken to accomplish this operation in a large enough flask toaccomodate the expansion of the foam.) TLC, R_(f) =0.25, silica gel,MeOH:CHCl₃ (5:95); R_(f) =0.37, silica gel, THF:toluene (20:80). Whenthe material is spotted lightly, the two isomers resolved to give spotsat R_(f) =0.37 and R_(f) =0.46, silica gel, THF:toluene (20:80).

(NOTE: Maintenance of the internal temperatures quoted in this procedureappears to be crucial for obtaining substantially pure product.)

d.2(RS),3(SR)-L-Valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

The product of Example 5c (131.6 g, 0.262 mol) was dissolved in EtOH(750 ml) and combined with 10% Pd/C catalyst (50% H₂ O, 13.0 g) under N₂in a large Parr hydrogenation bottle. The reaction mixture was shakenunder a 480,000 Pascals, 55 psi atmosphere of H₂ on a Parr apparatus.Repressurizing with H₂ was continued until no further uptake wasobserved. Examination of the reaction by TLC showed complete consumptionof starting material. The reaction mixture was filtered through Celite®and concentrated to a foam. This material was triturated with Et₂ O,filtered, and dried to give 81.4 g (84%) of light grey solid; TLC, R_(f)=0.41, silica gel, CHCl₃ :MeOH (10:1).

EXAMPLE 63S(orR)-Phenylmethoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═φCH₂, R⁴ ═H, A═OCO,n=1) a. 2R,3S-3-Amino-1,1,1-trifluoro-4-methyl-2-pentanol D-tartaricacid salt

Amine hydrochloride (20 g) generated as in Example 4e was dissolved inH₂ O and neutralized with solid NaHCO₃. The aqueous solution wasextracted several times with CH₂ Cl₂. The combined extracts were dried(Na₂ SO₄) and concentrated to yield the amine free base (14.04 g) as awhite solid. This material was combined with D-tartaric acid (12.31 g)in boiling anhydrous EtOH (100 ml), and the resultant cloudy solutionwas filtered hot through filter paper. The solution was first cooledslowly to room temperature overnight and then placed in the refrigeratorfor several hours. Precipitate was collected on a fritted funnel, washedwith cold EtOH, and dried overnight in a vacuum oven at 40°. A sample ofthe dried white solid (4.56 g) melted at 127°-130°. Most of thismaterial (4.05 g) was dissolved in boiling EtOH (20 ml), and thesolution was slowly cooled to room temperature. The white gel-like solidwhich deposited was collected in a sintered glass funnel and washed withseveral portions of EtOH. Vacuum oven drying at 40° C. for several hoursgave a white solid, m.p., 132°-134° C.

b. 2S,3S-[(Phenylmethoxy)carbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═φCH₂, R⁴ ═H, A═OCO,n=1)

Acid prepared according to Example 5b (1.00 g, 2.87 mmol) was dissolvedin dry THF (16 ml) under N₂ in a 50-ml, 3-necked, round-bottom flaskequipped with a thermometer, N₂ inlet, septum and a magnetic stir bar.NMM (0.34 ml, 3.09 mmol) was added and the resultant stirred solutionwas cooled to an internal temperature of -35°. Isobutyl chloroformate(0.37 ml, 2.85 mmol) was added over 2 min, never allowing the internaltemperature to rise above -35°. The reaction was stirred for 1 hr at-45° to -35°. The D-tartarate salt from Example 6a (0.92 g, 2.86 mmol)in a mixture of THF (5 ml) and DMSO (2 ml) was treated with NMM (0.68ml) and the cloudy solution was added to the reaction mixture at such arate that the temperature was kept below -40°. The reaction was stirredat -45° to -15° for 1 hr before it was allowed to warm to roomtemperature overnight. The mixture was diluted with CHCl₃ and thenwashed (H₂ O, sat'd aq NaHCO₃), dried (Na₂ SO₄), and concentrated togive the title product (1.15 g, 80%) as a white solid. The ¹ H-NMRspectrum of this material in DMSO-d₆ exhibited a doublet at δ6.43, whichis the appropriate chemical shift of the alcohol proton in material withthe assigned relative configuration.

c.3S(orR)-Phenylmethoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═φCH₂, R⁴ ═H, A═OCO,n=1).

A portion of the alcohol generated in Example 6b (0.25 g, 0.5 mmol) wasdissolved in CH₂ Cl₂ and treated with Dess-Martin periodinane (0.42 g,0.99 mmol) in a single portion. TFA (0.08 ml, 1.04 mmol) was added, andthe slightly turbid mixture was allowed to stir overnight. A whitesuspension formed in the reaction mixture. Starting material wassubstantially absent as demonstrated by TLC. Water containing Na₂ S₂ O₃(0.78 g) and NaHCO₃ (0.42 g) was added and stirred with the reactionmixture. When the organic layer eventually was cleared of the whitesolid suspension, it was separated from the aqueous phase. The organiclayer was washed (sat'd aq NaHCO₃), dried (Na₂ SO₄), and concentrated togive an oil. This material redissolved and was concentrated from Et₂O/hexane to give a white solid (0.21 g, 84% yield). Recrystallizationfrom hot Et₂ O/hexane yielded a substantially pure sample of the titlecompound as a substantially pure isomer which exhibited a single peak onHPLC with a retention time identical with that of an authentic sample ofthe title product prepared as described in Example 117; HPLC, t_(R)=5.65, Col A, H₂ O:CH₃ CH (55:45), FR=2.0

EXAMPLE 7 1-[2-(Tricyclo[3.3.1.1³,7]dec-1-yl)ethoxycarbonyl]-N-[3(RS)-3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidea. 4-Nitrophenyl 2-[tricyclo(3.3.1.1³,7)dec-1-yl]-ethyl carbonate

To a solution of p-nitrophenyl chloroformate (1.17 g, 5.82 mmol) in Et₂O (25 ml) at 0° C. was added pyridine (5 ml) followed by addition of2-(1-adamantyl)ethanol (1.00 g, 5.54 mmol) in Et₂ O (20 ml) dropwiseover 1 hr. The resulting mixture was stirred at room temperature for 12hr. and partitioned between H₂ O and Et₂ O. The ethereal layer waswashed with 5% aqueous HCl, pH 7.0 phosphate buffer, dried over MgSO₄,filtered and the solvents removed under vacuum. The crude product waspurified by flash chromatography on silica gel eluting with EtOAc:hexane(5:95) to give the product (1.10 g) as a white powder; TLC, R_(f) =0.29,silica gel, EtOAc:hexane (5:95).

b. 1-[2-(Tricyclo[3.3.1.1³,7]dec-1-yl)ethoxycarbonyl]-N-[2(RS),3(SR)-3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

A solution of the product of Example 7a (731.0 mg, 2.98 mmol), a productusing the procedure of Example 2b (500 mg, 1.80 mmol) and K₂ CO₃ (2.57g, 18.6 mmol) in DMF (50 ml) was stirred at room temperature for 18 hr.,filtered and the solvent removed under vacuum. The residue was taken upin EtOAc, washed with 3 portions of 10% aqueous NaOH, dried over solidK₂ CO₃ :Na₂ SO₄ (10:90), filtered and the solvent removed at reducedpressure. The crude product was chromatographed on silica gel elutingwith MeOH:CHCl₃ (1:99). The resulting solid was washed with hexane togive the product (340 mg) as a white solid; HPLC, t_(R) =5.86, 6.38,Zorbax® ODS analytical column, Flow rate=2 ml/min, CH₃ CN:H₂ O:TFA(70:30:0.1)

c. 1-[2-(Tricyclo[3.3.1.1³,7 ]dec-1-yl)ethoxycarbonyl]-N-3(RS)-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

To a solution of oxalyl chloride (1.09 g, 8.60 mmol) in dry CH₂ Cl₂ (15ml) cooled to -43° C. was added DMSO (1.37 g, 17.3 mmol) in dry CH₂ Cl₂(10 ml) dropwise over 15 min. The solution was stirred for 10 min. andthe product of Example 7b (340 mg, 0.72 mmol) was added in the samemanner over 30 min. After stirring the solution at -43° C. for anadditional 1 hr, TEA (4.80 ml, 34.5 mmol) was slowly added and thesolution allowed to warm slowly to room temperature and was stirred for2 hr. The solution was diluted with CH₂ Cl₂, washed with 10% aqueousHCl, 5% aqueous NaOCl, dried over solid K₂ CO₃ :Na₂ SO₄ (10:90),filtered and the solvent removed under vacuum. The crude product waspurified by 2 successive flash chromatographies on silica gel elutingwith MeOH:CHCl₃ (0.1:99.9) and EtOAc:hexane (1:5), respectively, to givethe product (130 mg) as a white solid; TLC, R_(f) =0.50, silica gel,MeOH:CHCl₃ (5:95); HPLC, t_(R) =5.31, Zorbax® ODS analytical column,flow rate=2 ml/min, CH₃ CN:H₂ O:TFA (70:30:.01).

Analysis calculated for: C₂₄ H₃₅ N₂ F₃ O₄.0.25H₂ O: C, 60.43; H, 7.50;N, 5.87. Found: C, 60.50; H, 7.45; N, 5.74.

EXAMPLE 83(RS)-1-(4-Phenylbutylcarbonyl)-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidea.2(RS),3(SR)-1-(4-Phenylbutylcarbonyl)-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

A solution of 5-phenylvaleric acid (0.330 g, 1.86 mmol) andN-methylmorpholine (0.280 g, 2.79 mmol) in THF (100 ml) was cooled to-15° C. A solution of isobutyl chloroformate (0.280 g, 2.05 mmol) in THF(5 ml) was added dropwise and the mixture was stirred at -15° C. for 10min., after which the temperature was lowered to -40° C. and a solutionof a product made using the procedure of Example 2b (0.500 g, 1.86 mmol)in THF (25 ml) was added dropwise. The mixture was stirred for 1 hr at-40° C. and overnight at room temperature. The mixture was filtered andthe filtrate concentrated under vacuum. The crude product was purifiedby flash chromatography on silica gel eluting with MeOH:CHCl₃ (3:97) togive the product (0.60 g) as a white solid; TLC, R_(f) =0.40-0.51,silica gel, MeOH: CHCl₃ (3:97).

b.3(RS)-1-(4-Phenylbutylcarbonyl)-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of DMSO (4.22 g, 54.0 mmol) in dry CH₂ Cl₂ (80 ml) was addeddropwise over 10 min to a pre-cooled (-60° C.), stirred solution ofoxalyl chloride (3.43 g, 27.0 mmol) in CH₂ Cl₂ (10 ml) under a nitrogenatmosphere. The temperature never exceeded -55° C. during the addition.The mixture was stirred at -60° C. for 15 min. and a solution of theproduct of Example 8a (0.580 g, 1.35 mmol) in CH₂ Cl₂ (100 ml) was addeddropwise over 10 min. at -60° C. The reaction mixture was stirred at-60° C. for 1 hr. Diisopropylethylamine (6.98 g, 54.0 mmol) was addeddropwise over 10 min at -60° C. The reaction mixture was stirred for 1hr as it warmed to room temperature. The reaction mixture was washedsuccessively with two portions of 1N aqueous HCl and brine, andconcentrated under vacuum to give the crude product (0.85 g) as anorange syrup. The crude product was purified by three successive flashchromatographies on silica gel eluting respectively with, 1) MeOH:CHCl₃(3:97), 2) MeOH:CHCl₃ (3:97), and 3) Et₂ O: hexane (90:10) to give theproduct (319 mg) as a white foam; TLC, R_(f) =0.33- 0.40, silica gel,Et₂ O: hexane (90:10); HPLC, t_(R) =17.93, 18.55, Zorbax® ODS analyticalcolumn, H₂ O:CH₃ CN (55:45), flow rate=2 ml/min.

Analysis calculated for: C₂₂ H₂₉ N₂ O₃ F₃.1.25H₂ O: C, 58.85; H, 7.07;N, 6.24. Found: C, 58.91; H, 6.83; N, 6.13.

EXAMPLE 9 3(RS)-1-[(Phenylmethoxy)carbonyl]-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of dimethylsulfoxide (0.890 g, 11.4 mmol) and dry methylenechloride (5 ml) was added dropwise to a stirred solution of oxalylchloride (0.75 g, 5.9 mmol) and dry methylene chloride (5 ml) at -60° C.under nitrogen. The reaction mixture was allowed to warm to -25° C.,then a solution of a product made using the process of Example 2a (0.200g, 0.497 mmol) and dry methylene chloride (5 ml) was added. Theresultant mixture was stirred at -25° C. for 0.5 hr. Triethylamine (1.94g, 19.2 mmol) was added and the reaction mixture was allowed to warm toroom temperature. The reaction mixture was filtered. The filtrate wasevaporated. The residue was dissolved in chloroform. The chloroformsolution was washed successively with 1N aqueous HCl, then brine anddried over Na₂ SO₄. The solution was filtered. The solvent was removedunder vacuum to give the crude product (0.147 g). The crude product waspurified by flash chromatography on silica gel with an eluent of CHCl₃ :MeOH (97:3) to give the product (0.11 g); TLC, R_(f) =0.25, CHCl₃ :EtOAc(90:10).

Analysis calculated for: C₁₉ H₂₃ F₃ N₂ O₄. 1.5H₂ O: C, 53.39; H, 6.13;N, 6.55. Found: C, 53.55; H, 5.78; N, 6.56.

EXAMPLE 102(RS),3(SR)-L-Valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamidea. N-[(Phenylmethoxy)carbonyl]-L-valyl-L-proline methyl ester

The procedure of Example 3a was repeated.

b. N-[(Phenylmethoxy)carbonyl]-L-valyl-L-proline

The procedure of Example 3b was repeated using the material from Example10a.

c. 2-Methyl-1-nitropropane

The procedure of Example 1a was repeated.

d. 2(RS),3(SR)-4-Methyl-3-nitro-1,1,1-trifluoro-2-pentanol

The procedure of Example 1b was repeated using the material from Example10c.

e. 2(RS),3(SR)-3-Amino-4-methyl-1,1,1-trifluoro-2-pentanol hydrochloridesalt

The procedure of Example 1c was repeated using the material from Example10d.

f. 2(RS),3(SR)-[(Phenylmethoxy)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl-L-prolinamide

The process of Example 3c was repeated using the compounds from Examples10b and 10e.

g. 2(RS),3(SR)-L-Valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

The process of Example 3d was repeated using the compound from Example10f.

EXAMPLE 113(RS)-[(Phenylmethoxy)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidea.-f. Steps a-f were repeated as explained in Examples 10a-f g.3(RS)-[(Phenylmethoxy)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of DMSO (12.46 g, 159.50 mmol) in dry CH₂ Cl₂ (12 ml) wasadded dropwise over 10 min. to a pre-cooled (-60° C.), stirred solutionof oxalyl chloride (10.12 g, 79.75 mmol) in CH₂ Cl₂ (160 ml) under anitrogen atmosphere. The temperature of the reaction never exceeded -50°C. during the addition. A solution of the alcohol in Example 11f (2.00g, 3.99 mmol) in CH₂ Cl₂ (160 ml) was added dropwise over 10 min. at-60° C. The reaction mixture was stirred at -60° C. for 1 hour.Diisopropylethylamine (20.62 g, 159.50 mmol) was added dropwise over 10min. at -60° C. The reaction mixture was stirred for 1 hr. as it warmedto room temperature. The reaction mixture was washed with 1N aqueousHCl, then brine, and then concentrated under vacuum to give the crudeproduct as an orange syrup (2.76 g). The crude product was purified withthree successive flash chromatographies on silica gel elutingrespectively with 1) ether:hexane (80:20), 2) MeOH:CHCl₃ (2.5:97.5), 3)MeOH:CHCl₃ (2.5: 97.5) to give the product as a white foam (0.88 g);TLC, R_(f) =0.45, silica gel, MeOH:CHCl₃ (3:97); HPLC, t_(R) =6.45,11.10, Zorbax® ODS analytical column, H₂ O: CH₃ CN (55:45) with 0.1%trifluoroacetic acid, flow rate=2 ml/min.

Analysis calculated for: C₂₄ H₃₂ N₃ O₅ F₃.0.5 H₂ O: C, 56.68; H, 6.54;N, 8.26. Found: C, 56.58; H, 6.52; N, 8.21.

EXAMPLE 123(RS)-[2-(2-Oxopyrrolidinyl)ethoxycarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxypentyl)]-L-prolinamidea. 4-Nitrophenyl-2-(2-oxopyrrolidinyl)ethyl carbonate

N-(2-hydroxyethyl)pyrrolidone (3.00 g, 23.2 mmol) was dissolved indiethyl ether (20 ml) under a nitrogen atmosphere and stirred at roomtemperature. A solution of p-nitrophenyl chloroformate (4.68 g, 23.2mmol) in diethyl ether (25 ml) was added dropwise to the mixture over 2hr. The mixture was stirred for an additional 2 hr. at room temperature.The mixture was concentrated under vacuum to give the crude product(7.90 g). The crude product was purified by flash chromatography onsilica gel with MeOH:CHCl₃ (5:95) to give the product as a white powder(4.62 g); TLC, R_(f) =0.51, silica gel, MeOH:CHCl₃ (3:97).

b.2(RS),3(SR)-[2-(2-Oxopyrrolidinyl)ethoxycarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

Potassium carbonate (2.820 g, 40.80 mmol) was added to a solution ofethyl-2-pyrrolidone-p-nitrophenyl carbonate (1.20 g, 4.08 mmol) and aproduct made using the procedure of Example 3d (1.50 g, 4.08 mmol) inDMF (100 ml) at room temperature under a nitrogen atmosphere. Thereaction was stirred overnight. The reaction mixture was diluted withEtOAc and the excess K₂ CO₃ was filtered. The filtrate was concentratedunder vacuum to give a residue which was dissolved in EtOAc and washedsuccessively with aqueous 10% NaHCO₃, water, aqueous 5% citric acid, andbrine. The organic phase was dried over Na₂ SO₄, filtered andconcentrated under vacuum to give the crude alcohol. The alcohol waspurified using flash chromatography on silica gel with MeOH:CHCl₃ (5:95)to give the product (0.72 g); TLC, R_(f) =0.46, silica gel, MeOH: CHCl₃(7:93).

c.3(RS)-[2-(2-Oxopyrrolidinyl)ethoxycarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxypentyl)]-L-prolinamide

A solution of DMSO (4.310 g, 55.20 mmol) in dry CH₂ Cl₂ (6 ml) was addeddropwise over 10 min. to pre-cooled (-60° C.), stirred solution ofoxalyl chloride (3.500 g, 27.60 mmol) in CH₂ Cl₂ (80 ml) under anitrogen atmosphere. The temperature of the reaction never exceeded -50°C. during the addition. A solution of the alcohol from Example 12b(0.720 g, 1.38 mmol) in CH₂ Cl₂ (80 ml) was added dropwise over 10 min.at -60° C. The reaction mixture was stirred at -60° C. for 1 hr. Asolution of diisopropylethyl amine (7.13 g, 55.2 mmol) in CH₂ Cl₂ (50ml) was added dropwise over 10 min. at -60° C. The reaction mixture wasstirred for 1 hr. as it warmed to room temperature. The reaction mixturewas washed with 1N aqueous HCl and brine and then concentrated undervacuum to give the crude product as an orange syrup. The crude productwas purified by flash chromatography on silica gel with MeOH:CHCl₃(5:95) to give the product as white foam (0.43 g) ; TLC, R_(f) =0.33,silica gel, MeOH:CHCl₃ (5:95); HPLC, t_(R) =3.50, 4.63, Zorbax® ODSanalytical column, H₂ O:CH₃ CN (55:45), flow rate=1 ml/min.

Analysis calculated for: C₂₃ H₃₅ N₄ O₆ F₃.H₂ O: C, 51.29; H, 6.92; N,10.40. Found: C, 51.20, H, 6.86; N, 10.03.

EXAMPLE 133(RS)-[2-Methoxycarbonyl)ethylcarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoromethyl-2-oxopentyl)]-L-prolinamidea. N-Benzyloxycarbonyl-L-valyl-L-proline t-butyl ester

A solution of N-benzyloxycarbonyl-L-valine (56.25 g, 0.244 mol) and HOBT(60.67 g, 0.45 mol) in DMF (565 ml) was cooled to 5° C. DCC (50.89 g,0.247 mol) was added in one portion. The mixture was stirred anadditional 15 min. at 5° C. and then L-proline t-butyl ester (38.36 g,0.224 mol) was added. The mixture was stirred an additional 2 hr. at 5°C. then for 48 hr. at room temperature. The mixture was filtered andconcentrated under vacuum. The oily residue was dissolved in EtOAc (1liter) and washed successively with 20% aqueous citric acid, saturatedaqueous NaHCO₃ and brine. The organic phase was dried over Na₂ SO₄,filtered and concentrated under vacuum to afford the product (92.0 g) asa white foam; TLC, R_(f) =0.9, silica gel, CHCl₃ :EtOAc (85:15).

b. L-Valyl-L-proline t-butyl ester

A mixture of the product of Example 13a (92.0 g, 0.227 mol) and 10% Pd/C(10 g) in EtOH (1 liter) was hydrogenated on a Parr shaker for 6 hr. at413,793.1 Pascals, 60 psi at room temperature. The mixture was filteredthrough Celite® and concentrated under vacuum to afford the product (62g) as a viscous yellow oil; TLC, R_(f) =0.3, silica gel, MeOH:CHCl₃(10:90).

c.N-[2-(Methoxycarbonyl)ethylcarbonyl]-L-valyl-L-proline-1,1-dimethylethylester

1N aqueous NaOH (8.0 ml) was added to a precooled (0° C.) solution ofthe product of Example 13b (2.1 g, 7.8 mmol) in CH₂ Cl₂ (60 ml). Themixture was stirred and 3-carbomethoxypropionyl chloride (0.96 ml, 7.8mmol) was added. The reaction was stirred vigorously for 15 min. at 0°C. The solution was removed from the ice bath, diluted with H₂ O (30 ml)and acidified with 1N aqueous HCl. The organic layer was separated andthe aqueous layer was extracted with CH₂ Cl₂. The organic layers werecombined, dried over Na₂ SO₄, filtered, and concentrated under vacuum.The resulting residue was purified by flash chromatography on a columnof silica gel eluting with Et₂ O followed by EtOAc to give the product(2.68 g); TLC, R_(f) =0.28, silica gel, Et₂ O.

d. N-[2-(Methoxycarbonyl)ethylcarbonyl]-L-valyl-L-proline

Trifluoroacetic acid (11.0 ml, 143 mmol) was added to a solution of theproduct of Example 13c (2.68 g, 6.98 mmol) in CH₂ Cl₂ (11 ml). Themixture was stirred for 4 hr. and concentrated under vacuum to give theproduct (2.13 g) which was used without further purification.

e.2(RS),3(SR)-[2-(Methoxycarbonyl)ethylcarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

Isobutylchloroformate (0.85 ml, 6.5 mmol) was added to a pre-cooled(-15° C.) solution of N-methylmorpholine (0.71 ml, 6.5 mmol) and theproduct of Example 13d (2.13 g, 6.5 mmol) in THF (50 ml). The reactionwas stirred for 10 min. and the temperature reduced to -50° C. Asuspension of N-methylmorpholine (0.71 ml, 6.5 mmol) and a product madeusing the procedure of Example 1c (1.39 g, 6.5 mmol) in THF (50 ml) wasadded in one portion and the reaction stirred overnight as it warmed toroom temperature. The reaction was filtered and the filtrateconcentrated under vacuum. The residue was taken up in EtOAc and washedsuccessively with 1N aqueous HCl and brine. The organic layer was driedover Na₂ SO₄, filtered and concentrated under vacuum. The resultingresidue was purified by flash chromatography on silica gel eluting withMeOH:CHCl₃ (5:95) to give the product (1.92 g); TLC, R_(f) =0.24, silicagel, MeOH:CHCl₃ (5:95).

f.3(RS)-[2-(Methoxycarbonyl)ethylcarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of DMSO (11.2 ml, 0.158 mol) in CH₂ Cl₂ (12 ml) was addedslowly to a pre-cooled (-60° C.) solution of oxalyl chloride (6.9 ml,0.079 mol) in CH₂ Cl₂ (160 ml). A solution of the product of Example 13e(1.90 g, 3.95 mmol) in CH₂ Cl₂ (160 ml) was added to the reactionmixture and stirred for 1 hr. at -60° C. Diisopropylethylamine (28.0 ml,0.158 mol) was added slowly and the reaction was allowed to warm toambient temperature. The solution was washed with 1N aqueous HCl (2×80ml) and brine. The organic layer was dried over Na₂ SO₄, filtered andconcentrated to give the crude product (3.5 g). The product was purifiedby filtration through silica gel with EtOAc followed by flashchromatography on silica gel using MeOH: CHCl₃ (5:95) to give theproduct (1.49 g); TLC, R_(f) =0.31, silica gel, MeOH:CHCl₃ (5:95);Diagnostic ¹ H NMR shifts (CD₃ SOCD₃, 250 MHz): 0.9, m, 12H; 3.54, s,3H; 3.54-3.68, m, 2H; 4.34, m, 1H; 4.40, m, 1H; 4.48 , dd, 1/2H; 4.58 ,dd, 1/2H; 8.1 , d, 1H; 8.58 , dd, 1H.

EXAMPLE 14

3(RS)-[(2-Carboxyethyl)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

1N aqueous NaOH (0.92 ml) was added to a solution of the product ofExample 13f (0.20 g, 0.42 mmol) in MeOH (10 ml) and the reaction wasstirred overnight at ambient temperature. 1N aqueous HCl (1 ml) wasadded and the reaction mixture was concentrated under vacuum to removeMeOH. The aqueous solution remaining was extracted with EtOAc and theorganic layer was washed with brine, dried over Na₂ SO₄, filtered andconcentrated under vacuum to give the product (0.18 g); TLC, R_(f) =0.2,silica gel, MeOH: CHCl₃ :TFA (5:94:1); HPLC, t_(R) =2.9, 5.86, AppliedScience Absorbosphere® C8, 4.6 mm×10 cm, CH₃ CN:H₂ O: TFA (20:80:0.1),flow rate=1.6 ml/min. EXAMPLE 153(RS)-[(4-(Ethoxycarbonyl)phenyl)aminocarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidea. 2 (RS),3(SR)-[(4-Ethoxycarbonylphenyl)aminocarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

A solution of ethyl 4-isocyanatobenzoate (0.86 g, 4.5 mmol) in CHCl₃ (2ml) was added dropwise to a solution of a product made using theprocedure of Example 3d (1.65 g, 4.5 mmol) in CHCl₃ (20 ml) and thereaction was stirred overnight at ambient temperature. The reaction wasconcentrated under vacuum to give the crude product. The product waspurified by flash chromatography on silica gel using MeOH:CHCl₃ (2.5:97.5) and MeOH:CHCl₃ (5:95) as eluents to give the product (1.76 g);TLC, R_(f) =0.34, silica gel, MeOH: CHCl₃ (5:95).

b. 3(RS)-[(4-Ethoxycarbonylphenyl)aminocarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of DMSO (4.5 ml, 63 mmol) in CH₂ Cl₂ (5 ml) was added slowlyto a pre-cooled (-60° C.) solution of oxalyl chloride (2.75 ml, 31.5mmol) in CH₂ Cl₂ (60 ml). The reaction was stirred for 15 min. at -60°C. A solution of the product of Example 15a (1.76 g, 3.15 mmol) in CH₂Cl₂ (60 ml) was added to the reaction mixture and stirred for 1 hr. at-60° C. Diisopropylethylamine (11 ml, 63 mmol) was added slowly and thereaction was allowed to warm to ambient temperature. The solution waswashed with 1N aqueous HCl (2×60 ml) and brine. The organic layer wasdried over Na₂ SO₄, filtered and concentrated under vacuum to give thecrude product (2.3 g). The product was purified by flash chromatographyon silica gel using a step gradient of CHCl₃, MeOH:CHCl₃ (2.5:97.5) andMeOH:CHCl₃ (5:95) to give the product (0.91 g); TLC, R_(f) =0.42, silicagel, MeOH:CHCl₃ (5:95); HPLC, t_(R) = 6.77, 11.27, Zorbax® ODSanalytical column, CH₃ CN:H₂ O (45:55), flow rate=2 ml/min.

EXAMPLE 163(RS)-[(4-Carboxyphenyl)aminocarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

1N aqueous NaOH (1 ml) was added to a solution of the product of Example15b (0.48 g, 0.86 mmol) in MeOH:H₂ O (8 ml:7 ml). The reaction wasstirred for 3 hr., additional 1N aqueous NaOH was added (1 ml) and thereaction was stirred overnight at ambient temperature. 1N aqueous HCl(2.5 ml) was added and the methanol was removed under vacuum. H₂ O (10ml) was added to the residue and extracted with EtOAc (2×50 ml). Thecombined organic layers were washed with brine, dried over Na₂ SO₄,filtered and concentrated under vacuum to give the product (0.42 g);TLC, R_(f) =0.17, silica gel, MeOH:CHCl₃ :AcOH (5:94:1); HPLC, t_(R)=2.38, 2.78, Zorbax® ODS analytical column, CH₃ CN:H₂ O (30:70), flowrate=1 ml/min.

EXAMPLE 173(RS)-[(4-Phenylbutyl)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide a. 2(RS),3(SR)-[(4-Phenylbutyl)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

DCC (0.906 g, 4.4 mmol) was added to a solution of 5-phenylvaleric acid(0.728 g, 4.08 mmol), a product made using the procedure of Example 3d(1.5 g, 4.08 mmol) and HOBT (1.19 g, 8.8 mmol) in THF (75 ml) at 0° C.The mixture was stirred and allowed to slowly warm to room temperatureovernight. The mixture was concentrated under vacuum and the resultingresidue was taken up in CHCl₃ (60 ml) and washed successively with 20%aqueous citric acid (30 ml), H₂ O (30 ml), 5% aqueous NaHCO₃ (30 ml) andbrine (30 ml). The organic phase was collected, dried over Na₂ SO₄,filtered and concentrated under vacuum to give the crude product (2.0g). Purification by flash chromatography on silica gel eluting withMeOH:CHCl₃ (5:95) gave the product (1.0 g) as a white foam; TLC, R_(f)=(0.5- 0.55), silica gel, MeOH: CHCl₃ (5:95).

b.3(RS)-[(4-Phenylbutyl)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of DMSO (3.4 ml, 48 mmol) in dry CH₂ Cl₂ (4 ml) was addeddropwise to a stirred solution of oxalyl chloride (2.10 ml, 24 mmol) indry CH₂ Cl₂ (50 ml) cooled to -60° C. under a N₂ atmosphere. Thesolution was stirred at -60° C. for 15 min. A solution of the product ofExample 17a (1.00 g, 1.89 mmol) in dry CH₂ Cl₂ (30 ml) was added slowly,keeping the solution temperature below -50° C. The mixture was stirredat (-50° C.) for 1 hr. Diisopropylethylamine (8.48 ml, 48 mmol) wasadded dropwise and the reaction mixture was allowed to warm slowly toroom temperature. The reaction mixture was washed successively with 1Naqueous HCl and brine. The organic phase was collected, dried with Na₂SO₄, filtered and concentrated under vacuum to give the crude ketone.The ketone was purified by 3 successive flash chromatographies withsilica gel and eluents of (MeOH:CHCl₃ (5:95), CHCl₃ (100%)--MeOH:CHCl₃(3:97), and Et₂ O (100%)--MeOH:Et₂ O (10:90) to give the final product(0.2 g) as a white waxy solid; HPLC, t_(R) =6.80, 8.90, Zorbax® ODScolumn; H₂ O:CH₃ CN:TFA (40:60:0.1), flow rate=0.75 ml/min.

Analysis calculated for: C₂₇ N₃ O₄ F₃ H₃₈.0.5 H₂ O: C, 60.65; H, 7.35;N, 7.85. Found: C, 60.68; H, 7.30; N, 7.67.

EXAMPLE 18 3 (RS)-2-[2-(Tricyclo[3.3.1.1³,7]dec-1-yl)ethoxycarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidea. 4-Nitrophenyl 2-(tricyclo[3.3.1.1³,7 ]dec-1-yl)ethyl carbonate

A product was obtained using the process of Example 7a.

b. 2(RS),3(SR)-[2(Tricyclo[3.3.1.1³,7]dec-1-yl)ethoxycarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

A solution of the product of Example 18a (0.758 g, 2.19 mmol), a productmade using the procedure of Example 3d (0.768 g, 2.09 mmol) and K₂ CO₃(2.89 g, 20.9 mmol) in DMF (75 ml) was stirred at room temperature for18 hr., filtered, and the solvents removed under vacuum. The residue wasdiluted with ethyl acetate, washed with 3 portions of 10% aqueous NaOHand brine, dried over solid K₂ CO₃ :Na₂ SO₄ (10:90), filtered and thesolvents removed at reduced pressure. The crude product was purified byflash chromatography on silica gel, eluting with MeOH:CHCl₃ (2:98) togive the product (0.965 g) as a white foam; TLC, R_(f) =0.14 and 0.18,silica gel, MeOH:CHCl₃ (2:98).

c. 3(RS)-[2-(Tricyclo[3.3.1.1³,7]dec-1-yl)ethoxycarcarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

To a solution of oxalyl chloride (2.14 g, 16.8 mmol) in dry CH₂ Cl₂ (30ml) cooled to -43° C. was added DMSO (2.66 g, 33.6 mmol) in CH₂ Cl₂ (20ml) dropwise over 1 hr., followed by addition of the product of Example18b (0.965 g, 1.68 mmol) in the same manner over 30 min. After stirringthe solution at -43° C. an additional 1 hr., triethylamine (8.50 g, 84.0mmol) was added and the solution allowed to warm slowly to roomtemperature. The solution was diluted with CH₂ Cl₂, washed with 5%aqueous HCl, 5% aqueous NaOCl, dried over MgSO₄, filtered and thesolvent removed under vacuum. The crude product was purified by flashchromatography on silica gel eluting with CHCl₃ after pretreating silicagel with MeOH:CHCl₃ (1:99) to give the product (410 mg) as a white foam;TLC, R_(f) =0.39, silica gel, MeOH:CHCl₃ (2:98); HPLC t_(R) =8.12 and10.75, Zorbax® ODS column, flow rate=1.5 ml/min., CH₃ CN:H₂ O:TFA(70:30: 0.1).

Analysis calculated for: C₂₉ H₄₄ N₃ F₃ O₅.0.75 H₂ O: C, 59.52; H, 7.83;N, 7.18. Found: C, 59.48; H, 7.70; N, 7.17.

EXAMPLE 193(RS)-[(2-Methoxyethoxy)ethoxycarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidea. 2-(2-Methoxyethoxy)ethyl 4-nitrophenyl carbonate

To a solution of p-nitrophenyl chloroformate (2.00 g, 9.92 mmol) in Et₂O (50 ml) at 0° C. was added pyridine (8 ml), followed by addition of2-(2-methoxyethoxy)ethanol (1.14 g, 9.45 mmol) in Et₂ O (25 ml) dropwiseover 1 hr. The resulting mixture was stirred at room temperature for 12hr. and partitioned between H₂ O and Et₂ O. The ethereal layer waswashed with 5% aqueous HCl, pH 7.0 phosphate buffer, dried over MgSO₄,filtered and the solvents removed under vacuum. The crude product waspurified by flash chromatography on silica gel eluting with EtOAc:hexane(30:70) to give the product (1.30 g) as a clear colorless oil; TLC,R_(f) =0.11, silica gel, EtOAc:hexane (30:70).

b.2(RS),3(SR)-[(2-Methoxyethoxyethoxy)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

A solution of the product from Example 19a (1.11 g, 3.90 mmol), aproduct made using the procedure of Example 3d (1.37 g, 3.72 mmol), andK₂ CO₃ (5.14 g, 37.2 mmol) in DMF (100 ml) was stirred at roomtemperature for 18 hr., filtered and the solvents removed under vacuum.The residue was taken up in ethyl acetate, washed with 3 portions of 10%aqueous NaOH and brine, dried over solid K₂ CO₃ :Na₂ SO₄ (10:90),filtered and the solvents removed under vacuum. The crude product waspurified by flash chromatography on silica gel, eluting with EtOAc afterpretreating the silica gel with TEA:hexane (1:9) to give the product(1.13 g) as a clear colorless glass; TLC, R_(f) =0.43 and 0.48, silicagel, MeOH:CHCl₃ (1:9).

Analysis calculated for: C₂₂ H₃₈ N₃ O₇ F₃ : C, 51.45; H, 7.45; N, 8.18.Found: C, 51.48, H, 7.35; N, 8.01.

c.3(RS)-[(2-Methoxyethoxy)ethoxycarbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

To a solution of oxalyl chloride (3.26 g, 2.57 mmol) in dry CH₂ Cl₂ (70ml) cooled to -43° C. was added DMSO (4.07 g, 51.4 mmol) in CH₂ Cl₂ (20ml) dropwise over 1 hr., followed by the addition of the product ofExample 19b (1.10 g, 2.14 mmol) in CH₂ Cl₂ (25 ml) in the same mannerover 30 min. After stirring the solution at -43° C. for an additional 1hr., TEA (10.80 g, 107.0 mmol) was added and the solution allowed towarm slowly to room temperature. The solution was diluted with CH₂ Cl₂,washed with 5% aqueous HCl, 5% aqueous NaOCl, dried over MgSO₄, filteredand the solvents removed under vacuum. The crude product was purified byflash chromatography on silica gel, eluting with MeOH:CHCl₃ (2:98) togive the product (420 mg) as a clear, light yellow syrup; TLC, R_(f)=0.32 and 0.37, silica gel, MeOH:CHCl₃ (5:95); HPLC, t_(R) =7.38 and9.55, Zorbax® ODS analytical column, flow rate=0.5 ml/min, CH₃ CN:H₂ O:TFA (50:50:0.1).

Analysis calculated for: C₂₂ H₃₆ N₃ O₇ F₃ 0.75 H₂ O: C, 50.33; H, 7.20;N, 8.00. Found: C, 50.34; H, 7.21; N, 7.58.

EXAMPLE 20 3(RS) -[(4-Methoxyphenyl)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide a.2(RS),3(SR)-[(4-Methoxyphenyl)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

To a solution of a product made using the procedure of Example 3d (1.50g, 4.08 mmol) and TEA (2.06 g, 20.4 mmol) in CHCl₃ (50 ml) cooled to 0°C., was added 4-methoxybenzoyl chloride (0.766 g, 4.49 mmol) in CHCl₃(40 ml) dropwise over 1 hr. and the solution stirred at room temperatureovernight. The solvents were removed under vacuum and the residue takenup in EtOAc, washed with 5% aqueous HCl, 20% aqueous NaOH, dried oversolid K₂ CO₃ :Na₂ SO₄ (10:90), filtered, and the solvents removed undervacuum. The crude product was purified by flash chromatography on silicagel, eluting with MeOH:CHCl₃ (5:95) to give the product (1.84 g) as awhite foam; TLC, R_(f) =0.33, silica gel, MeOH:CHCl₃ (5:95).

Analysis calculated for: C₂₄ H₃₄ O₅ N₃ F₃ 0.3 H₂ O: C, 56.86; H, 6.88;N, 8.29. Found: C, 56.80; H, 6.88; N, 8.07.

b.3(RS)-[(4-Methoxyphenyl)carbonyl]-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

To a solution of oxalyl chloride (3.79 g, 29.9 mmol) in dry CH₂ Cl₂ (50ml) cooled to -43° C. was added DMSO (4.73 g, 59.8 mmol) in CH₂ Cl₂ (20ml) dropwise over 40 min., followed by addition of the product ofExample 20a (1.50 g, 2.99 mmol) in CH₂ Cl₂ (20 ml) in the same mannerover 30 min. After stirring the solution at -43° C. for an addition 1hr., TEA (15.10 g, 149.5 mmol) was added and the solution allowed towarm slowly to room temperature. The solution was diluted with CH₂ Cl₂,washed with 5% aqueous HCl, 5% aqueous NaOCl, dried over MgSO₄, filteredand the solvents removed under vacuum. The crude product was purified byflash chromatography on silica gel, eluting with EtOAc: hexane (1:1)after pretreating the silica gel with TEA:hexane (10:90) to give theproduct (489 mg) as a white foam; TLC, R_(f) =0.15 and 0.19silica gel,MeOH:CHCl₃ (2:98); HPLC t_(R) =6.62 and 9.72, Zorbax® ODS column, flowrate=1 ml/min., CH₃ CN:H₂ O:TFA (50:50:0.1).

Analysis calculated for: C₂₄ H₃₂ O₅ N₃ F₃ : C, 57.71; H, 6.46; N, 8.41.Found: C, 57.39; H, 6.67; N, 8.18.

EXAMPLE 21 3 (RS)-N²,N⁶ -Di [(phenylmethoxy)carbonyl]-L-lysyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide a.2(RS),3(SR)-N-[3-(4-Methyl-1,1,1-trifluoro-2-hyadroxypentyl)]-L-prolinamide

A product using the process of Example 2b was obtained.

b. 2(RS),3(SR)-N²,N⁶ -Di[(phenylmethoxy)carbonyl]-L-lysyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

DCC (0.84 g, 4.09 mmol) was added to a stirred solution of (N²,N⁶-dibenzyloxycarbonyl)-L-lysine (1.54 g, 3.72 mmol), the product ofExample 21a (1.0 g, 3.72 mmol), 1-hydroxybenzotriazole (1.01 g, 7.44mmol), and dry THF (70 ml) at 0° C. under nitrogen. The reaction mixturewas stirred at 0° C. for 1 hr. and allowed to warm to room temperatureslowly overnight. The reaction mixture was filtered, the solvent removedunder vacuum and the residue dissolved in CHCl₃. The CHCl₃ solution waswashed with 20% aqueous citric acid, the organic layer was dried overNa₂ SO₄ and filtered. The solvent was removed under vacuum to give thecrude product (3.14 g). The product was purified by flash chromatographyon silica gel eluting with CHCl₃ :MeOH, (97:3) to afford 1.50 g of thefinal product, R_(f) =0.33-0.45, CHCl₃ :MeOH (95:5), silica gel.

c. 3(RS)-N²,N⁶-Di[(phenylmethoxy)carbonyl]-L-lysyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of DMSO (3.59 g, 46 mmol) and dry CH₂ Cl₂ (30 ml) was addedto a stirred solution of oxalyl chloride (3.04 g, 24 mmol) and dry CH₂Cl₂ (50 ml) at -60° C. under nitrogen. The reaction mixture was stirredat -60° C. for 5 min. and was allowed to warm to -30° C. A solution ofthe product of Example 21b (1.32 g, 2.0 mmol) and dry CH₂ Cl₂ (30 ml)was added dropwise. The resultant reaction mixture was stirred at -25°C. for 1 hr. TEA (7.8 g, 77.4 mmol) was added and the reaction mixturewas allowed to slowly warm to room temperature. The reaction mixture waswashed with 1N aqueous HCl, and brine. The organic layer was dried overNa₂ SO₄, filtered, and the solvent removed under vacuum to give theproduct (2.6 g). The product was purified by flash chromatography(silica gel, CHCl₃ :MeOH, 97:3, to afford the product (0.99 g); TLC,R_(f) =0.4-0.52, CHCl₃ :MeOH (95:5), silica gel.

EXAMPLE 223(RS)-[(Phenylmethoxy)carbonyl]-L-phenylalanyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidea.2(RS),3(SR)-[(Phenylmethoxy)carbonyl]-L-phenylalanyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

DCC (1.01 g, 4.92 mmol) was added to a stirred solution of a portion ofthe product of Example 21a (1.41 g, 4.47 mmol),N-(benzyloxycarbonyl)-L-phenylalanine (1.20 g, 4.47 mmol),1-hydroxybenzotriazole (1.21 g, 8.94 mmol) and dry THF (75 ml) at 0° C.under nitrogen. The reaction mixture was stirred at 0° C. for 1 hr. andallowed to warm to room temperature and was stirred overnight. Thereaction mixture was filtered and the solvent removed under vacuum togive the crude residue which was dissolved in CHCl₃. The CHCl₃ solutionwas washed with 20% aqueous citric acid and brine, and dried over Na₂SO₄. The CHCl₃ solution was filtered and the solvent removed undervacuum to give the crude product (3.57 g). The product was purified byflash chromatography on silica gel, eluting with CHCl₃ :MeOH (97:3) togive the product (1.45 g) as a white foam; TLC, R_(f) = 0.39-0.60, CHCl₃:MeOH (95:5), silica gel, HPLC:Zorbax® ODS analytical column, CH₃ CN:H₂O (50:50), flow rate=2.5 ml/min., t_(R) =6.47 and 7.63.

b.3(RS)-[(Phenylmethoxy)carbonyl]-L-phenylalanyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of DMSO (2.33 g, 29.9 mmol) and dry CH₂ Cl₂ (40 ml) was addeddropwise to a stirred solution of oxalyl chloride (1.89 g, 14.9 mmol)and dry CH₂ Cl₂ (40 ml) at -60° C. under nitrogen. The reaction wasstirred at -60° C. for 0.5 hr. A solution of the product of Example 22a(1.43 g, 2.49 mmol) and dry CH₂ Cl₂ (40 ml) was added at -50° C. Theresultant mixture was stirred at -60° C. for 1 hr. Diisopropylethylamine(7.70 g, 59.7 mmol) was added and the reaction mixture was allowed towarm to room temperature. The mixture was washed twice with 1N aqueousHCl, then brine. The organic layer was dried over Na₂ SO₄, filtered andthe solvent was removed under vacuum to give the crude product (1.87 g).The product was purified by flash chromatography on silica gel, CHCl₃:MeOH (98:2) to give the product (0.771 g) as a white foam; TLC, R_(f)=0.62-0.69, CHCl₃ :MeOH (95:5), silica gel; HPLC:Zorbax® ODS analyticalcolumn, CH₃ CN:H₂ O (50:50), flow rate=2.5 ml/min., t_(R) =6.11 and6.21.

Analysis calculated for: C₂₈ H₃₂ F₃ N₃ O₅ : C, 61.41; H, 5.84; N, 7.67.Found: C, 61.53; H, 5.82; N, 7.67.

EXAMPLE 233(RS)-[2-(Methoxycarbonyl)ethylcarbonyl]-L-norleucyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidea. N-[2-(Methoxycarbonyl)ethylcarbonyl]-L-norleucine

A solution of 1N sodium hydroxide (100 ml, 100 mmol) was added dropwiseto a vigorously stirred mixture of L-norleucine (6.55 g, 50 mmol) andmethylene chloride (250 ml) at 0° C. under nitrogen.3-Carbomethoxypropionyl chloride (7.52 g, 50 mmol) was added dropwise.The resultant reaction mixture was stirred at 0° C. for 15 min. Thecooling bath was removed and water (100 ml) was added. The pH wasadjusted to 1 with 3N aqueous HCl. Ethyl acetate (200 ml) was added andthe organic layer was separated. The aqueous layer was extracted withethyl acetate and the organic layers were combined, washed with brineand dried over Na₂ SO₄. The solution was filtered. The solvent wasremoved under vacuum to give the crude product (10.73 g). A portion ofthe crude product (6.47 g, 6.4 mmol) was purified by flashchromatography on silica gel, CHCl₃ :MeOH, (97:3) to give the product(5.31 g); TLC, R_(f) =0.45, silica gel, CHCl₃ :MeOH:AcOH (95:4.75:0.25).

b.2(RS),3(SR)-[2-(Methoxycarbonyl)ethylcarbonyl]-L-norleucyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

Dicyclohexylcarbodiimide (3.46 g, 16.8 mmol) was added to a pre-cooled(0° C.) solution of a product made using the procedure of Example 3d(5.60 g, 15.3 mmol), the product of Example 23a (3.75 g, 15.3 mmol) and1-hydroxybenzotriazole (4.13 g, 30.6 mmol) in THF (70 ml). The resultingsolution was allowed to warm slowly to room temperature and stirredovernight. The reaction was filtered and concentrated under vacuum. Theresidue was diluted with EtOAc and the resulting solution washed withsaturated aqueous NaHCO₃ and brine, dried over Na₂ SO₄, filtered andconcentrated under vacuum to give the crude product. The product waspurified by flash chromatography on a column of silica gel using aseluent a gradient of Et₂ O (100%), Et₂ O: EtOAc (90:10), Et₂ O: EtOAc(75:25), Et₂ O: EtOAc (50:50) to give the product (5.6 g); TLC, R_(f)=0.45, silica gel, MeOH:CHCl₃ (1:9).

c.3(RS)-[2-(Methoxycarbonyl)ethylcarbonyl]-L-norleucyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of DMSO (27.0 ml, 0.378 mol) in CH₂ Cl₂ (27 ml) was addedslowly to a pre-cooled (-65° C.) solution of oxalyl chloride (16.5 ml,0.189 mol) in CH₂ Cl₂ (350 ml). The resulting solution was stirred for15 min. and a solution of the product of Example 23b (5.60 g, 0.00943mol) in CH₂ Cl₂ (250 ml) was added. The reaction was stirred for 1 hr.at -65° C. and diisopropylethylamine (67.0 ml, 0.378 mol) was addeddropwise. The reaction was allowed to warm to room temperature and wasthen washed with 1N aqueous HCl and brine, dried over Na₂ SO₄, filteredand concentrated under vacuum to give the crude product. The crudeproduct was purified by flash chromatography on a column of silica geleluting with a stepwise gradient of Et₂ O (100%), Et₂ O: EtOAc (50:50),EtOAc (100%) to give a partially purified product which was furtherpurified by flash chromatography on silica gel eluting with a stepwisegradient of CHCl₃ (100%), MeOH:CHCl₃ (2.5:97.5) and MeOH:CHCl₃ (5:95) togive the final product (3.24 g); HPLC, t_(R) =6.80 and 12.98, Zorbax®ODS analytical column, H₂ O:CH₃ CN (65:35), flow rate=2 ml/min.

EXAMPLE 243(RS)-[(2-Carboxyethyl)carbonyl]-L-norleucyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

1N aqueous NaOH (9.5 ml) was added to a solution of the product ofExample 23c (2.60 g, 4.39 mmol) in MeOH (95 ml). The reaction wasstirred overnight at room temperature and 1N aqueous HCl (10.5 ml) wasadded. The reaction was concentrated under vacuum and H₂ O (35 ml) wasadded. The suspension was extracted with EtOAc and the organic layer waswashed with brine, dried over Na₂ SO₄, filtered and concentrated undervacuum to give the product (2.1 g). HPLC, t_(R) =12.63 and 19.05,Zorbax® ODS analytical column, H₂ O:CH₃ CN (65:35), flow rate=0.5ml/min.

EXAMPLE 253(RS)-[(Phenylmethoxy)carbonyl]-L-alpha-glutamyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidephenylmethyl ester a.2(RS),3(SR)-[(Phenylmethoxy)carbonyl]-L-alpha-glutamyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamidephenylmethyl ester

Isobutylchloroformate (0.53 ml, 4.1 mmol) was added to a pre-cooled(-15° C.) solution of N-benzyloxycarbonyl-L-glutamic acid-α-benzyl ester(1.52 g, 4.1 mmol) and N-methylmorpholine (0.45 ml, 4.1 mmol) in THF (30ml). The reaction mixture was stirred for 10 min. and then cooled to-40° C. A solution of the product of Example 3d (1.5 g, 4.1 mmol) in THF(30 ml) was added dropwise and the reaction was stirred overnight andallowed to warm slowly to room temperature. The reaction was filteredand concentrated under vacuum. The residue was taken up in EtOAc, washedwith 1N aqueous HCl and brine, dried over Na₂ SO₄, filtered andconcentrated to give the crude product. The product was purified byflash chromatography on a column of silica gel using as eluant agradient of CHCl₃ (100%), MeOH:CHCl₃ (2.5:97.5) and MeOH:CHCl₃ (5:95) togive the product (2.13 g); TLC, R_(f) =0.43, silica gel, MeOH:CHCl₃(5:95).

b.3(RS)-[(Phenylmethoxy)carbonyl]-L-alpha-glutamyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidephenylmethyl ester

A solution of DMSO (8.40 ml, 0.118 mol) in CH₂ Cl₂ (8 ml) was addedcarefully to a pre-cooled (-65° C.) solution of oxalyl chloride (5.2 ml,0.059 mol) in CH₂ Cl₂ (100 ml). The solution was stirred for 15 min. anda solution of the product of Example 25a (2.13 g, 2.96 mmol) in CH₂ Cl₂(100 ml) was added dropwise. The reaction was stirred for 1 hr at -60°C. and N,N-diisopropylethylamine (20.9 ml, 0.118 mol) was addeddropwise. The reaction was allowed to warm to room temperature, washedwith 1N aqueous HCl and brine, dried over Na₂ SO₄, filtered andconcentrated to give the crude product. The product was partiallypurified by flash chromatography on a column of silica gel using aseluant a stepwise gradient of Et₂ O (100%), Et₂ O: EtOAc (50:50) andEtOAc (100%). The product was finally purified by flash chromatographyon a column of silica gel using as eluant a stepwise gradient of CHCl₃(100%), MeOH:CHCl₃ (1:99), MeOH:CHCl₃ (2:98), MeOH:CHCl₃ (3:97) andMeOH:CHCl₃ (5:95) to give the product (1.35 g); HPLC, t_(R) =7.2 and11.5, Zorbax® ODS analytical column, H₂ O:CH₃ CN (50:50), flow rate=2ml/min.

EXAMPLE 26 3(RS)-N² -[2-(Methoxycarbonyl)ethylcarbonyl]-N⁶-[(phenylmethoxy)carbonyl]-L-lysyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidea. N² -[(2-Methoxycarbonyl)ethylcarbonyl]-N₆ -phenylmethoxycarbonyllysine

1N aqueous NaOH (43 ml) was added to a pre-cooled (0° C.) solution ofN-benzyloxycarbonyl-L-lysine (6.06 g, 0.0216 mol) in CH₂ Cl₂ (160 ml).The reaction was vigorously stirred and 3-carbomethoxypropionyl chloride(2.66 ml, 0.0216 mol) was added. The reaction was vigorously stirred for15 min at 0° C. Water (100 ml), 1N aqueous HCl (25 ml) and EtOAc (500ml) were added successively and the layers were separated. The organiclayer was washed with brine, dried over Na₂ SO₄, filtered andconcentrated to give the product (6.78 g). The product was used withoutfurther purification.

b. 2(RS),3(SR)-N² -[2-(Methoxycarbonyl)ethylcarbonyl]-N⁶-phenylmethoxycarbonyl-L-lysyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

DCC (2.85 g, 13.9 mmol) was added to a mixture of a product made usingthe procedure of Example 3d (4.63 g, 12.6 mmol), the product of Example26a (5.00 g, 12.6 mmol), and HOBT (3.76 g, 27.8 mmol) in THF (65 ml)pre-cooled to 0° C. The mixture was stirred at 0° C. for 1 hr., warmedto room temperature and stirred overnight. The solvent was removed undervacuum, the residue diluted with EtOAc and washed successively withsaturated NaHCO₃ and brine. The organic phase was dried over solid K₂CO₃ :Na₂ SO₄ (10:90), filtered, and the solvent removed under vacuum togive the crude product. Purification by flash chromatography on silicagel with an eluent of MeOH:CHCl₃ (1:99) gave the product (6.22 g) as awhite foam; TLC, R_(f) =0.40, silica gel, MeOH:CHCl₃ (5:95).

c. 3(RS)-N² -[2-(Methoxycarbonyl)ethylcarbonyl]-N⁶-[(phenylmethoxy)carbonyl]-L-lysyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of DMSO (15.9 g, 100 mmol) in dry CH₂ Cl₂ (50 ml) was addeddropwise to a stirred solution of oxalyl chloride (8.8 ml, 200 mmol) indry CH₂ Cl₂ (150 ml) cooled to -43° C. under nitrogen. A solution of theproduct of Example 26b (6.22 g, 8.37 mmol) in CH₂ Cl₂ (60 ml) was addedin the same manner. The reaction mixture was stirred at -20° C. for 1 hrand TEA (70 ml, 400 mmol) was added dropwise. The mixture was allowed toslowly warm to room temperature, stirred for an additional 1 hr and thendiluted with CH₂ Cl₂, washed with 5% aqueous NaOCl, dried over solid K₂CO₃ :Na₂ SO₄ (10:90) filtered and the solvent removed under vacuum togive the crude product. Purification by flash chromatography on silicagel with an eluent of MeOH:CHCl.sub. 3 (1:99) gave the product (4.5 g)as a light yellow foam; TLC, R_(f) =0.51, silica gel, MeOH: CHCl₃ (1:9);HPLC, t_(R) =6.99 and 12.01, flow rate=1 ml/min, Zorbax® ODS analyticalcolumn, H₂ O: CH₃ CN: TFA (50:50:0.1).

EXAMPLE 27 3(RS)-N² -[(2-Carboxyethyl)carbonyl]-N⁶-[(phenylmethoxy)carbonyl]-L-lysyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of the product of Example 26c (2.0 g, 2.7 mmol) in MeOH (60ml) and IN NaOH (5.4 ml, 5.4 mmol) was stirred at room temperature for12 hr. and then taken to pH 7 with 1N aqueous HCl (6.0 ml, 6.0 mmol).The MeOH was removed under vacuum; the resulting residue was dissolvedin EtOAc, washed with brine, dried over MgSO₄, filtered and the solventremoved under vacuum to give the crude product. Purification by flashchromatography on silica gel (pH 5.5, Baker®) with chloroform gave theproduct (1.7 g) as a white foam; HPLC, t_(R) =4.06 and 5.56, flow rate=1ml/min, Zorbax® ODS analytical column, H₂ O:CH₃ CN:TFA (50:50:0.1).

Analysis calculated for: C₃₄ H₄₈ N₅ O₉ F₃.1.75 H₂ O: C, 53.78; H, 6.83;N, 9.22. Found: C, 53.46; H, 6.39; N, 9.03.

EXAMPLE 28 3S(orR)-N²,N⁶-Di[(phenylmethoxy)carbonyl]-L-lysyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamidea. 2(RS),3(SR)-N²,N⁶-Di[(phenylmethoxy)carbonyl]-L-lysyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-hydroxypentyl)]-L-prolinamide

DCC (0.93 g, 4.49 mmol) was added to a stirred solution of N²⁻,N⁶-benzyloxycarbonyl-L-lysine (1.69 g, 4.08 mmol), a product made usingthe procedure of Example 3d (1.50 g, 4.08 mmol), 1-hydroxybenzotriazole(1.10 g, 8.16 mmol) and dry THF (75 ml) at 0° C. under nitrogen. Thereaction mixture was stirred at 0° C. for 1 hr., then was allowed towarm to room temperature and was stirred overnight. The reaction mixturewas filtered. The filtrate was evaporated under vacuum. The residue wasdissolved in CHCl₃ and the solution was washed with 1N aqueous HCl andbrine and was dried over Na₂ SO₄. The Na₂ SO₄ was filtered and thefiltrate was concentrated under vacuum to give the crude product (3.94g) which was purified by flash chromatography on silica gel, CHCl₃ :MeOH(95:5), to give 2.48 g of product; TLC, R_(f) =0.36-0.56, CHCl.sub. 3:MeOH (95:5), silica gel; HPLC, Zorbax® ODS analytical column, flowrate=1.5 ml/min, CH₃ CN:H₂ O (50:50); t_(R) =18.33, 14.99.

Analysis calculated for: C₃₃ H₄₁ F₃ N₄ O₇ : C, 59.01; H, 6.24; N, 8.45.Found: C, 58.89; H, 6.33; N, 7.89.

b. 3S(orR)-N²,N⁶-Di[(phenylmethoxy)carbonyl]-L-lysyl-L-valyl-N-[3-(4-methyl-1,1,1-trifluoro-2-oxopentyl)]-L-prolinamide

A solution of DMSO (2.8 g, 36.13 mmol) and dry CH₂ Cl₂ (40 ml) was addedto a stirred solution of oxalyl chloride and dry CH₂ Cl₂ (40 ml) at -60°C. under nitrogen. Then a solution o f the product of Example 28a, (2.30g, 3.01 mmol) and dry CH₂ Cl₂ (40 ml) was added to the reaction mixtureat -50° C. The resultant reaction mixture was stirred at -60° C. for 1hr. Triethylamine (7.290 g, 72.26 mmol) was added and the reaction wasallowed to warm to room temperature. The mixture was washed twice with1N aqueous HCl, then brine and was dried over Na₂ SO₄. The Na₂ SO₄ wasfiltered and the filtrate was concentrated under vacuum to give thecrude product (2.67 g). The product was purified by flash chromatographyon silica gel with an eluent of CHCl₃ : MeOH (97:3) to afford 64 mg ofproduct; TLC, R_(f) =0.6, CHCl₃ :MeOH (95:5); HPLC, Zorbax® ODSanalytical column, CH₃ CN:H₂ O (60:40), flow rate=1.5 ml/min, t_(R)=5.29.

Analysis calculated for: C₃₈ H₅₀ F₃ N₅ O₈. H₂ O: C, 58.53; H, 6.72; N,8.98. Found: C, 58.95; H, 6.59; N, 8.74.

EXAMPLE 29 3 (RS)-1-(12-Methoxy-12-oxododecyloxy)carbonyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═CH₃ OCO(CH₂)11, A═OCO, n=1) a. Methyl12-hydroxydodecanoate

A mixture of 1-hydroxydodecanoic acid (4.0 g, 18.5 mmol), MeOH (450 ml),conc H₂ SO₄ (2.5 ml), and 3A molecular sieves (3 ml) was stirred atreflux for 16 hr. The mixture was neutralized with satd aq NaHCO₃,concentrated under vacuum, and partitioned between Et₂ O and water. Theethereal solution was washed (water, sat'd aq NaHCO₃, brine), dried (Na₂SO₄), filtered, and concentrated under vacuum to give the product (3.94g) as a white solid; NMR (DMSO-d₆) δ3.65 (3H,s); 1.7-1.0 (22H,m).

b. 11-Methoxycarbonylundecyl 4-nitrophenyl carbonate

Using the method of Example 7a, the product of Example 29a was convertedinto the title compound and purified by flash chromatography(EtOAc:hexane (1:9)) to obtain the title compound in 59% yield; TLC,R_(f) =0.20, EtOAc:hexane (1:9).

c.2(RS),3(SR)-1-(12-Methoxy-12-oxododecyloxy)carbonyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═CH₃ OCO(CH₂)₁₁, A═OCO, n=1)

Using the method of Example 7b, the product of Example 29b was allowedto react with material prepared using the method of Example 2b toprovide, after purification by flash chromatography (acetone:hexane(3:7)), the title product (45%); HPLC, t_(R) =4.43, Col A, CH₃ CN:H₂ O(35:65), FR=2.0.

d. 3 (RS)-1-(12-Methoxy-12-oxododecyloxy)carbonyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═CH₃₀ CO(CH₂)₁₁, A═OCO, n=1)

To the product of Example 29c (1.1 mmol) was added DMSO (65 ml) and Ac₂O (50 mmol). The resulting solution was stirred 18 hr at roomtemperature and diluted with Et₂ O. The organic solution was washed(satd aq NaHCO₃ (3×), water, and brine), dried (Na₂ SO₄), filtered,concentrated under vacuum, and purified by flash chromatography (Et₂ O:hexane (1:1)) to afford the title product (100%); HPLC, t_(R) =12.73,Col A, CH₃ CN:H₂ O (60:40), FR=2.0.

Analysis calculated for: C₂₂ H₂₈ F₃ N₃ O₅.0.4H₂ O: C, 55.91; H, 8.00; N,5.21. Found: C, 56.05; H, 8.00; N, 5.19.

EXAMPLE 30 3 (RS)-1-(12-Hydroxy-12-oxododecyloxy)carbonyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═HOCO(CH₂)₁₁, A═OCO, n=1)

Using the method of Example 14 the product of Example 29d was convertedinto the title product, purified by flash chromotography (EtOAc:hexane(1:1)) and obtained in 10% yield; HPLC, t_(R) =4.55, Col A, CH₃ CN:H₂ O(60:40), FR=2.0.

Analysis calculated for: C₂₄ H₃₉ F₃ N₂ O₆.O.1H₂ O: C, 56.48; H, 7.74; N,5.49. Found: C, 56.48; H, 7.96; N, 5.23.

EXAMPLE 313(RS)-1-[1-Oxo-5-(phenylmethoxycarbonylamino)pentyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ OCONH(CH₂)₄, A═CO, n=1) a.5-(Phenylmethoxycarbonylamino)valeric acid

To a stirred, cooled solution (0°) of 5-amino valeric acid (5.00 g,42.68 mmol) and 2N NaOH (32.0 ml, 32.0 mmol) was added simultaneouslybenzyl chloroformate (7.65 g, 6.40 ml, 44.81 mmol) and 2N NaOH (32.0 ml,32.0 mmol). After stirring at 0° for 0.5 hr, the solution was washedwith Et₂ O. The Et₂ O layer was acidified to pH 2.0 with 6N HCl,resulting in the product's precipitating out of solution. The titlecompound was filtered, washed (H₂ O) and dried (vacuum oven) to give thepure product as a white solid (8.55 g, 80.0%), mp 104°-105° ; TLC, R_(f)=0.48, MeOH:CHCl₃ :AcOH (3:97:0.1).

b.2(RS),3(SR)-1-[1-Oxo-5-(phenylmethoxycarbonylamino)pentyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ OCONH(CH₂)₄, A═CO, n=1).

To a stirred, cooled solution (0°) of the product of Example 31a (0.47g, 1.86 mmol), HOBT (0.50 g, 3.72 mmol), and DCC (0.40 g, 1.95 mmol) inCHCl₃ (50 ml) was added product prepared using the method of Example 2b(0.50 g, 1.86 mmol). After the reaction mixture had stirred overnight atroom temperature, it was filtered and concentrated to afford a syrupwhich was partially dissolved in EtOAc. The insoluble material wasfiltered from the EtOAc solution before it was washed (satd aq NaHCO₃,5% aq citric acid, and brine), dried (Na₂ SO₄), and concentrated to amixture which was purified by flash chromatography (MeOH:CHCl₃ (4:96))to give the title product as a white foam (0.78 g, 84%); TLC, R_(f)=0.4, MeOH:CHCl₃ (4:94).

c. 3(RS)-1-[1-Oxo-5-(phenylmethoxycarbonylamino)pentyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (Formula Ia,R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ OCONH(CH₂)₄, A═CO, n=1)

To the product of Example 31b (1 mmol) was added DMSO (85 mmol) and Ac₂O (64 mmol). The resulting solution was stirred for 18 hr at roomtemperature, poured into ice water (50 ml) and stirred for 1 to 4 hr.The crude product was extracted into EtOAc; and the EtOAc solution waswashed (satd aq NaHCO₃, brine), dried (Na₂ SO₄), filtered, andconcentrated under vacuum before the product was purified by flashchromatography (CHCl₃ :MeOH (97:3)) to afford the product (58%); HPLC,t_(R) =6.56 & 7.79, Col A, H₂ O:CH₃ CN (60:40), FR=2.0.

Analysis calculated for: C₂₄ H₃₂ F₃ N₃ O₅. 1.5H₂ O: C, 54.74; H, 6.69;N, 7.98. Found: C, 54.87; H, 6.20; N, 8.02.

EXAMPLE 32 3(RS)-1-(1-Oxo-4-phenoxybutyl)-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φO(CH₂)₃, A═CO, n=1) a.2(RS),3(SR)-1-(1-Oxo-4-phenoxybutyl)-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═φO(CH₂)₃, A═CO, n=1)

To a 0.25M solution of 4-phenoxybutanoic acid in THF was added a molarequivalent amount of CDI in one portion. After the reaction mixture wasstirred for 1 hr at room temperature, an molar equivalent amount ofproduct prepared using the method of Example 2b was added in oneportion. After the reaction was stirred overnight, excess satd aq NaHCO₃was added; and the mixture was extracted with EtOAc. The EtOAc extractswere washed (in HCl, brine), dried (MgSO₄), filtered, and concentratedunder vacuum to afford the title product (88%); TLC, R_(f) =0.53 & 0.61,MeOH: CH₂ Cl₂ (1:9).

b.3(RS)-1-(1-Oxo-4-phenoxybutyl)-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φO(CH₂)3, A═CO, n=1).

By the method of Example 31c, the product of Example 32 a was convertedinto the title compound in 39% yield after crystallization from water;TLC; R_(f) =0.68 & 0.6 4, CH₂ Cl₂ :MeOH (9:1).

Analysis calculated for: C₂₁ H₂₇ F₃ N₂ O₄.1.25 H₂ O: C, 55.93; H, 6.59;N, 6.21. Found: C, 55.88; H, 6.67; N, 6.15.

EXAMPLE 333(RS)-1-[2-(4-Morpholinyl)ethoxycarbonyl]-N-[3-1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═4-morpholinyl-(CH₂)₂, A═OCO, n=1) a.2-(4-Morpholinyl)ethyl 4-nitrophenyl carbonate hydrochloride

Using the method of Example 7a but with the omission of the pyridine(and of the acid wash), 2-(4-morpholinyl)ethanol was treated with4-nitrophenyl chloroformate. The crude product was filtered, washed withEt₂ O, and dried under vacuum. The product obtained (91%) was used forthe subsequent reaction without further characterization.

b.2(RS),3(SR)-1-[2-(4-Morpholinyl)ethoxycarbonyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpenytyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═4-morpholinyl-(CH₂)₂, A═OCO, n=1)

Using the method of Example 7b, the product of Example 33a was allowedto react with product prepared using the method of Example 2b toprovide, after purification by flash chromatography (MeOH:CHCl₃ (1:99)),the title product (68%); TLC, R_(f) =0.34, MeOH: CHCl₃ (5:95), FR=2.0.

c.3(RS)-1-[2-(4-Morpholinyl)ethoxycarbonyl]-N-[3-1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═4-morpholinyl-(CH₂)₂, A═OCO, n=1)

To the product (1.1 mmol) of Example 33b was added DMSO (65 mmol) andAc₂ O (50 mmol). The resulting solution may be stirred 18 hr at roomtemperature and diluted with CH₂ C12. The organic solution may be washed(satd aq NaHCO₃ (3×), water, and brine), dried (Na₂ SO₄), filtered andconcentrated under vacuum before purification by flash chromatography(MeOH: CHCl₃ (2:98)) to provide the title product; HPLC, t_(R) =8.44 &9.88, Col A, CH₃ CN:H₂ O (60:40), FR=2.0.

Analysis calculated for: C₁₈ H₂₈ F₃ N₃ O₅.1.OH₂ O: C, 48.97; H, 6.85; N,9.51. Found: C, 48.97; H, 6.61; N, 9.73.

EXAMPLE 343(RS)-1-[1-Oxo-6-[2-(2-pyridyl)ethoxy]carbonylaminohexyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═(2-pyridyl)--(CH₂)₂ OCONH--(CH₂)₅,A═CO, n=1) a. 4-Nitrophenyl 2-(2-pyridyl)ethyl carbonate

A solution of 2-pyridinethanol (1.38 g, 11 mmol) in Et₂ O (20 mol) wasadded over 1 hr to a stirred solution of p-nitrophenylchloroformate(2.26 g, 11 mmol) at 0° under nitrogen. The resulting mixture wasstirred for 1 hr at 0° before the precipitate which had formed wascollected under a blanket of nitrogen and recrystallized from absoluteEtOH to give 1.53 g (58%) of the title compound as off-white crystals,mp 125°-127°.

b.2(RS),3(SR)-1-[1-Oxo-6-[2-(2-pyridyl)ethoxy]carbonylaminohexyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═(2-pyridyl)(CH₂)₂ OCONH(CH₂)₅, A═CO,n=1)

A solution of the amine product of Example 50b (0.75 g, 1.8 mmol), theproduct of Example 34a (0.675 g, 1.8 mmol), TEA (0.52 ml, 3.6 mmol), CH₃CN (25 ml) and water (25 ml) was stirred at room temperature for 2 daysbefore the solvent was removed under vacuum to afford the crude productwhich was purified by flash chromatography (CH₃ OH:CHCl₃ (2.5:97.5) toprovide the product (1.13 mmol, 60%) as a pale yellow solid; TLC, R_(f)=0.5, CH₃ OH:CHCl₃ (5:95).

c.3(RS)-1-[1-Oxo-6-[2-(2-pyridyl)ethoxy]carbonylaminohexyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═(2-pyridyl)--(CH₂)₂ OCONH(CH₂)₅, A═CO,n=1).

Using the method of Example 31c, the product of Example 34c wasconverted into the title product to afford, after purification by flashchromatography (MeOH:CH₂ Cl₂ (3:97)) the title product in 10% yield;HPLC, t_(R) =1.84, Col A, H₂ O:CH₃ CN (60:40), FR=2.0.

Analysis calculated for: C₂₅ H₃₅ F₃ N₄ O₅.0.5H₂ O: C, 55.85; H, 6.75; N,10.40. Found: C, 56.08; H, 6.82; N, 10.43.

EXAMPLE 35 3(RS)-1-[2-Phenylmethoxy-1-(phenylmethoxymethyl)ethoxycarbonyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═(φCH₂ OCH₂)₂ CH, A═OCO, n=1) a.4-Nitrophenyl 2-phenylmethoxy-1-(phenylmethoxymethyl)ethyl carbonate

TEA (0.74 g, 7.34 mmol) was added dropwise to a stirred solution ofp-nitrophenylchloroformate (1.48 g, 7.34 mmol) and Et₂ O (30 ml) between0° and 5°. To the above reaction mixture a solution of1,3-dibenzylglycerol (2.0 g, 7.34 mmol) and Et₂ O (20 ml) was addedbetween 0° and 5°, and the resulting mixture was stirred for 2 hrbetween 0° and 5° before it was allowed to warm to room temperature andstirred overnight. The reaction mixture was filtered and concentratedunder vacuum to leave 3.6 g of yellow oil which was purified by flashchromatography (hexane:Et₂ O (8:2)) to give 2.19 g (68%) of the titlecompound as a clear oil; TLC, R_(f) =0.33, hexane:ether (7:3).

b.2(RS),3(SR)-1-[2-Phenylmethoxy-1-(phenylmethoxymethyl)ethoxycarbonyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═(φCH₂ OCH₂)CH, A═OCO, n=1).

Using the method of Example 7b, product of Example 35a was allowed toreact with the product prepared using the method of Example 2b toprovide, after purification by flash chromatography (CHCl₃ :EtOAc(95:5)), the title product (62%); HPLC, t_(R) =5.81 & 6.29, Col A, H₂O:CH₃ CN (40:60), FR=2.0.

c.3(RS)-1-[2-Phenylmethoxy-1-(phenylmethoxymethyl)ethoxycarbonyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═(φCH₂ OCH₂)₂ CH, A═OCO, n=1)

Using the method of Example 31c, the product of Example 35b was oxidizedto afford, after purification by flash chromatography (CHCl₃ :EtOAc(98:2)), the title product (13%); HPLC, t_(R) =5.62, Col A, H₂ O:CH₃ CN(40:60), FR=2.0.

Analysis calculated for: C₂₉ H₃₅ F₃ N₂ O₆.0.25H₂ O: C, 61.20; H, 6.28;N, 4.92. Found: C, 61.28; H, 6.34; N, 5.15.

EXAMPLE 363(RS)-1-[1-Oxo-4-(1-oxo-2-phenoxyethylamino)butyl]-N-3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φOCH₂ CONH(CH₂)₃, A═CO, n=1) a. Ethyl4-(1-oxo-2-phenoxyethylamino)butanoate

To a stirred mixture of ethyl 4-aminobutanoate hydrochloride (3.4 g) andphenoxyacetyl chloride (2.76 ml) in 50 ml of Et₂ O and 50 ml of waterwas added one portion of NaHCO₃ (4.2 g). After 2 hr the layers wereseparated and the organic phase was washed (1N HCl, brine), dried(MgSO₄), and filtered. Evaporation of the solvent under vacuum gave 3.1g (53%) of the title compound as an oil.

b. 4-(1-Oxo-2-phenoxyethylamino)butanoic acid

A mixture of the product of Example 36a (3.1 g) in 1N NaOH (15 ml) wasstirred for 6 hr at room temperature. The resulting solution was madeacidic with 2N HCl. The solid which precipitated was collected, washedwith water and dried under high vacuum. There was obtained 2.5 g (95%)of the title compound as a white solid, mp. 91°-94°.

c.2(RS),3(SR)-1-[1-Oxo-4-(1-oxo-2-phenoxyethylamino)butyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═φOCH₂ CONH(CH₂)₃, A═CO, n=1)

Using the method of Example 32a, the product of Example 36b was allowedto react with product prepared using the method of Example 2b toprovide, after purification by an acid and base wash workup, the titleproduct (92%); TLC, R_(f) =0.43 & 0.48, MeOH:CH₂ Cl₂ (1:9).

d.3(RS)-1-[1-Oxo-4-(1-oxo-2-phenoxyethylamino)butyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φOCH CONH(CH₂) A═CO n=1)

Using the method of Example 61c, the product of Example 36d was oxidizedto afford, after purification by flash chromatography (MeOH: CH₂ Cl₂(3:97)), the title product (75%); HPLC, t_(R) =4.62 & 6.02, Col A, CH₃CN :H₂ O (65: 35), FR=2.0.

Analysis calculated for: C₂₃ H₃₀ F₃ N₃ O₅ : C, 56.26; H, 6.28; N, 8.56.Found: C, 56.28; H, 6.40; N, 8.30.

EXAMPLE 373(RS)-1-(4-Methoxy-1,4-dioxobutyl)-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═CH₃ OCO(CH₂)₂, A═CO, n=1) a.2(RS),3(SR)-1-(4-Methoxy-1,4-dioxobutyl)-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═CH₃ OCO(CH₂)₂, A═CO ,n=1).

To a stirred mixture of product prepared using the method of Example 2b(1.34 g) in CH₂ Cl₂ (50 ml) and 1N NaOH (6 ml) cooled in an ice-waterbath was added dropwise 3-carbomethoxypropionyl chloride (0.75 g). After1 hr the layers were separated and the organic phase was dried (Na₂SO₄), filtered and evaporated to provide 1.1 g (58%) of the titlecompound as a white powder; TLC, R_(f) =0.57, MeOH:CH₂ Cl₂ (1:9).

b.3(RS)-1-(4-Methoxy-1,4-dioxobutyl)-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═CH₃ OCO(CH₂)₂, A═CO, n=1)

Using the method of Example 61c, the product of Example 37a was oxidizedto afford, after purification by flash chromatography (MeOH:CH₂ Cl₂(2:98)), the title product (71%); TLC, R_(f) =0.58, MeOH: CH₂ Cl₂ (1:9).

Analysis calculated for: C₁₆ H₂₃ F₃ N₂ O₅.0.75H₂ O: C, 48.79; H, 6.27;N, 7.11. Found: C, 49.04; H, 6.12; N, 6.83.

EXAMPLE 383(RS)-1-[3-(1,1-Dimethylethoxycarbonyl)amino-1-oxopropyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═(CH₃)₃ COCONH(CH₂)₂, A═CO, n=1) a.2(RS),3(SR)-1-[3-(1,1-Dimethylethoxycarbonyl)amino-1-oxopropyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═(CH₃)₃ COCONH(CH₂)₂, A═CO, n=1).

Using the method of Example 32a, 3-(BOC-amino)propanoic acid was allowedto react with product prepared using the method of Example 2b to providethe title product (80%); TLC, R_(f) =0.35, MeOH:CH₂ Cl₂ (1:9).

b.3(RS)-1-[3-(1,1-Dimethylethoxycarbonyl)amino-1-oxopropyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═(CH₃)₃ COCONH(CH₂)₂, A═CO, n=1)

Using the method of Example 61c, the product of Example 38a was oxidizedto afford, after purification by flash chromatography (MeOH:CH₂ Cl₂(2:98)), the named product (61%); TLC, R_(f) =0.46, MeOH: CH₂ Cl₂ (1:9).

Analysis calculated for: C₁₉ H₃₀ F₃ N₃ O₅. 0.75H₂ O: C, 50.83; H, 6.62;N, 9.39. Found: C, 51.18; H, 7.00; N, 9.28.

EXAMPLE 393(RS)-1-(3-Benzoylamino-1-oxopropyl)-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φCONH(CH₂)₂, A═CO, n=1) a.2(RS),3(SR)-1-(3-Benzoylamino-1-oxopropyl)-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═φCONH(CH₂)₂, A═CO, n=1)

Using the method of Example 32a, 3-(benzoylamino)propanoic acid wasallowed to react with product prepared using the method of Example 2b toprovide the title product (83%); TLC, R_(f) =0.39 & 0.42, MeOH:CH₂ Cl₂(1:9).

b.3(RS)-1-(3-Benzoylamino-1-oxopropyl)-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φCONH(CH₂)₂, A═CO, n=1)

Using the method of Example 61c, the product of Example 39a was oxidizedto afford, after purification by flash chromatography (MeOH:CH₂ Cl₂(2:98)), the title product (48%); TLC, R_(f) =0.54, MeOH:CH₂ Cl₂ (1:9).

Analysis calculated for: C₂₁ H₂₆ F₃ N₃ O₄ : C, 57.14; H, 5.94; N, 9.52.Found: C, 57.12; H, 6.59; N, 9.45.

EXAMPLE 403(RS)-1-[3-(1-Oxo-2,2-diphenylethyl)amino]-1-oxobutyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φ₂ CHCONH(CH₂)₃, A═CO, n=1) a. Ethyl3-(1-oxo-2,2-diphenylethyl)aminobutanoate

To a stirred solution of ethyl 4-aminobutyrate hydrochloride (2.51 g)and diphenylacetyl chloride (3.46 g) in 50 ml of CH₂ Cl₂ was added 50 mlof water followed by the addition of one portion of NaHCO₃ (3.4 g).After 2 hr the layers were separated and the organic phase dried (Na₂SO₄), filtered and evaporated. There was obtained 3.5 g (72%) of thetitle compound as a white solid; TLC, R_(f) =0.71, MeOH: CH₂ Cl₂ (5:95).

b. 3-(1-Oxo-2,2-diphenylethyl)aminobutanoic acid

A mixture of the product of Example 40a (3.5 g) in 1N NaOH (30 ml) andEtOH (10 ml) was stirred for 10 hr. The solution was then extracted withEt₂ O. The aqueous phase was made acidic with 2N HCl; and theprecipitated solid was collected, washed with water and dried under highvacuum. There was obtained 2.9 g (93%) of the title compound as a whitepowder.

c.2(RS),3(SR)-1-[3-(1-Oxo-2,2-diphenyethyl)amino-1-oxobutyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═φ₂ CHCONH(CH₂)₃, A═CO, n=1).

Using the method of Example 32a, the product of Example 40b was allowedto react with product prepared using the method of Example 2b to providethe title product (81%); TLC, R_(f) =0.13, MeOH:CH₂ Cl₂ (5:95).

d.3(RS)-1-[3-(1-Oxo-2,2-diphenylethyl)amino-1-oxobutyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φ₂ CHCONH(CH₂)₃, A═CO, n=1)

Using the method of Example 61c, the product of Example 40c was oxidizedto afford, after purification by flash chromatography (MeOH:CH₂ Cl₂(2:98)), the title product (27%); TLC, R_(f) =0.24, MeOH: CH₂ Cl₂(5:95).

Analysis calculated for: C₂₉ H₃₄ F₃ N₃ O₄.1.OH₂ O: C, 61.31; H, 6.48; N,7.39. Found: C, 61.58; H, 6.77; N, 7.43.

EXAMPLE 413(RS)-1-[2-(2-Methoxyethoxy)ethoxycarbonyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═CH₃ O(CH₂)₂ O(CH₂)₂, A═OCO, n=1) a.2(RS),3(SR)-1-[2-(2-Methoxyethoxy)ethoxycarbonyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═CH₃ O(CH₂)₂ O(CH₂)₂, A═OCO, n=1)

Using the method of Example 7b, the product of Example 19a was allowedto react with product prepared using the method of Example 2b toprovide, after purification by dry column flash chromatography oversilica gel using gradient elution with acetone: hexane from (10:90) to(50:50), the title product (75%); TLC, R_(f) =0.30 & 0.35,acetone:hexane (40:60).

b.3(RS)-1-[2-(2-Methoxyethoxy)ethoxycarbonyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═CH₃ O(CH₂)₂ OCH₂)₂, A═OCO, n=1)

Using the method of Example 61c, the product of Example 41a was oxidizedto afford, after purification by flash chromatography (acetone:CHCl₃(1:3)), the title product (42%); HPLC, t_(R) =5.69, Col A, H₂ O: CH₃ CN(75:25), FR=2.0.

Analysis calculated for: C₁₇ H₂₇ F₃ N₂ O₆ : C, 49.39; H, 6.83; N, 6.78.Found: C, 49.27; H, 6.80; N, 6.48.

EXAMPLE 423(RS)-1-[1,4-Dioxo-4-(phenylmethylamino)butyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φCH NHCO(CH₂) A═CO n=1) a.4-Oxo-4-(phenylmethylamino)butanoic acid

A mixture of benzyl amine (10.7 g) and succinic anhydride (10 g) wasstirred in THF (1 liter) for 2 days. The solid was filtered anddissolved in 1N NaOH (110 ml). The aqueous phase was washed with Et₂ Oand then made acidic with conc HCl while cooling in an ice-water bath.The solid was collected, washed with water and dried under high vacuum.There was obtained 10.9 g (53%) of the title compound as a white powderm. p. 137.5°-138°.

b.2(RS),3(SR)-1-[1,4-Dioxo-4-(phenylmethylamino)butyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ NHCO(CH₂)₂, A═CO, n=1)

Using the method of Example 32a, the product of Example 42a was allowedto react with product prepared using the method of Example 2b to providethe title compound (74%); TLC, R_(f) =0.48, MeOH:CH₂ Cl₂ (1:9).

c.3(RS)-1-[1,4-Dioxo-4-(phenylmethylamino)butyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ NHCO(CH₂)₂, A═CO, n=1)

Using the method of Example 61c, the product of Example 42b was oxidizedto afford, after purification by flash chromatography (MeOH:CH₂ Cl₂(2:98)), the title product (40%); TLC, R_(f) =0.56, MeOH: CH₂ Cl₂ (1:9).

Analysis calculated for: C₂₂ H₂₈ F₃ N₃ O₄ : C, 58.10; H, 6.20; N, 9.23.Found: C, 57.90; H, 6.36; N, 9.27.

EXAMPLE 433(RS)-1-[1-Oxo-3-(phenylmethoxycarbonylamino)propyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia R¹ ═CH(CH₃)CH₃, R³ ═φCH OCONH(CH₂)₂, A═CO, n=1) a.2(RS),3(SR)-1-[1-Oxo-3-(phenylmethoxycarbonylamino)propyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═φCH OCONH(CH₂) A═CO n=1)

Using the method of Example 32a, CBZ-β-alanine was allowed to react withproduct prepared using the method of Example 2b to provide the titleproduct (82%); TLC, R_(f) =0.59, MeOH:CH₂ Cl₂ (1:9).

b.3(RS)-1-[1-Oxo-3-(phenylmethoxycarbonylamino)propyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ OCONH(CH₂)₂, A═CO, n=1)

Using the method of Example 61c, the product of Example 43a was oxidizedto afford, after purification by flash chromatography (MeOH:CH₂ Cl₂(2:98)), the title product (35%); TLC, R_(f) =0.23, MeOH: CH₂ Cl₂(5:95).

Analysis calculated for: C₂₂ H₂₈ F₃ N₃ O₅.0.4H₂ O: C, 55.20; H, 6.06; N,8.77. Found: C, 55.28; H, 6.25; N, 8.55.

EXAMPLE 443(RS)-1-[1-Oxo-4-(phenylmethoxycarbonylamino)butyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ OCONH(CH₂)₃, A═CO, n=1) a.2(RS),3(SR)-1-[1-Oxo-4-(phenylmethoxycarbonylamino)butyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═φCH OCONH(CH₂)₃, A═CO, n=1)

Using the method of Example 32a, CBZ-4-aminobutanoic acid was allowed toreact with product prepared using the method of Example 2b to providethe title product (7290); TLC, R_(f) =0.47, Et₂ O:EtOAc (1:1).

b.3(RS)-1-[1-Oxo-4-(phenylmethoxycarbonylamino)butyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ OCONH(CH₂)₃, A═CO, n=1)

Using the method of Example 61c, the product of Example 44a was oxidizedto afford, after purification by preparative TLC (MeOH:CHCl₃(2.5:97.5)), the title product (329°); TLC, R_(f) =0.65 & 0.68,MeOH:CHCl₃ (1:9)

EXAMPLE 453R(orS)-1-[1-Oxo-4-phenoxy-2-(2-phenoxyethyl)butyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═[φO(CH₂)₂ ]₂ CH A═CO, n=1) a. Diethyl2,2-di(2-phenoxyethyl)malonate

To a stirred solution of sodium (2.3 g) in absolute EtOH (50 ml) wasadded diethyl malonate (15.2 ml) followed by 2-phenoxyethyl chloride(15.7 g). The reaction mixture was then refluxed for 12 hr. The EtOH wasevaporated under vacuum and the mixture diluted with water (40 ml). Theaqueous phase was extracted with Et₂ O. The combined Et₂ O extracts werewashed (brine), dried (MgSO₄) filtered and evaporated. Bulb to bulbdistillation afforded 12.2 g (27%) of the title diester as a clearliquid, bp 155°-175° (106 Pascals, 0.8 Torr); TLC, R_(f) =0.34, CH₂ Cl₂.

b. 4-Phenoxy-2-(2-phenoxyethyl)butanoic acid

A mixture of the product of Example 45a (10.0 g) and potassium hydroxide(17.7 g) in water (22 ml) was refluxed for 4 hr. The reaction mixturewas cooled and acidified with conc HCl. The precipitated solid wascollected, washed with water and air dried. The solid obtained (8.44 g)was heated at 170° for 2 hr and then cooled. Recrystallization of thesolid from cyclohexane gave 4.1 g (93%) of the title compound as finewhite needles; mp 85°-86°.

Analysis calculated for: C₁₈ H₂₀ O₄ : C, 71.98; H, 6.71. Found: C,71.92; H, 6.71.

c. 4-Phenoxy-2-(2-phenoxyethyl)butanoyl chloride

A mixture of the product of Example 45b (1.5 g) and thionyl chloride(0.73 ml) was heated on a steam bath for 1 hr. The reaction mixture wasthen stripped. The acid chloride title product was obtained as a clearoil in quantitative yield and was used directly.

d.2(RS),3(SR)-1-[1-Oxo-4-phenoxy-2-(2-phenoxyethyl)butyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═[φO(CH₂)₂ ]₂ CH, A═CO, n=1)

Using the method of Example 37a, the product of Example 45c was allowedto react with product prepared using the method of Example 2b to providethe title product (95%); TLC, R_(f) =0.47 & 0.54, Et₂ O.

e. 3R(orS)-[1-Oxo-4-phenoxy-2-(2-phenoxyethyl)butyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia R¹ ═CH(CH₃)CH₃, R³ ═[φO(CH₂)₂ ]₂ CH, A═CO, n=1)

Using the method of Example 61c, the product of Example 45d was oxidizedto afford the crude product as a mixture of diastereomers which wasseparated by flash chromatography (Et₂ O:hexane (gradient elution, 60:40to 75:25)). The faster eluting diastereomer was the title compound,obtained in 27.7% yield; HPLC, t_(R) =6.94, Col A, CH₃ CN:H₂ O (65:35),FR=2.0.

Analysis calculated for: C₂₉ H₃₅ F₃ N₂ O₅ : C, 63.49; H, 6.43; N, 5.11.Found: C, 63.39; H, 6.47; N, 5.07.

EXAMPLE 46 3S(orR)-[1-Oxo-4-phenoxy-2-(2-phenoxyethyl)butyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═[φO(CH₂)₂ ]₂ CH, A═CO, n=1)

From the separation of the diastereomers of the crude product describedin Example 45e, the slower eluting diastereomer was the title compoundhere, obtained in 28.3% yield; HPLC, t_(R) =5.04, Col A, CH₃ CH: H₂ O(65:35), FR=2.0.

Analysis calculated for: C₂₉ H₃₅ F₃ N₂ O₅ : C, 63.49; H, 6.43; N, 5.11.Found: C, 63.50; H, 6.45; N, 5.26.

EXAMPLE 473(RS)-1-[6-[(4-Ethoxycarbonylphenyl)aminocarbonylamino]-1-oxo]hexyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide (Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═4-(CH₃ CH₂OCO)φNHCONH(CH₂)₅, A═CO, n=1) a.2(RS),3(SR)-1-[6-[(4-Ethoxycarbonylphenyl)aminocarbonylamino]-1-oxo]hexyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═4-(CH₃ CH₂ OCO)ONHCONH(CH₂)₅, A═CO,n=1)

Ethyl p-isocyanatobenzoate (0.288 g, 1.5 mmol) was added to a stirredsolution of the product of Example 50b (0.6 g, 1.5 mmol), TEA (0.15 g,1.5 mmol), and DMF (20 ml) under nitrogen at room temperature. Theresulting mixture was stirred at room temperature overnight before itwas concentrated under vacuum to leave an amber residue which wasdissolved in EtOAc. The EtOAc solution was washed (1N HCl), dried(MgSO₄), filtered, and concentrated under vacuum to leave 1.15 g of oilyresidue. This residue was purified by flash chromatography (CHCl₃ :CH₃OH (97:3)) to give 0.62 g (70%) of the title compound as a white solid;TLC, R_(f) =0.28 & 0.35, CHCl₃ :CH₃ OH (95:5).

b.3(RS)-1-[6-[(4-Ethoxycarbonylphenyl)aminocarbonylamino]-1-oxo]hexyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═4, (CH₃ CH₂ OCO)ONHCONH(CH₂)₅, A═CO,n=1)

Using the method of Example 61c the product of Example 47a was oxidizedto afford, after purification by flash chromatography (CHCl₃ :MeOH(97:3)), the title product (43%); HPLC, t_(R) =12.39 & 15.79, Col. A, H₂O:CH₃ CN (65:35), FR=2.0.

Analysis calculated for: C₂₇ H₃₇ F₃ N₄ O₆.1.0H₂ O: C, 55.09; H, 6.68; N,9.51. Found: C, 54.75; H, 6.63; N, 9.29.

EXAMPLE 483(RS)-1-[6-(Phenylmethoxycarbonylamino)-1-oxohexyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ OCONH(CH₂)₅, A═CO, n=1)

Using the method of Example 31c, the product of Example 50a was oxidizedto afford, after purification by flash chromatography (CHCl₃ :MeOH(97:3)), the title product (31%); HPLC, t_(R) =4.06, Col. A, CH₃ CN:H₂ O(1:1), FR=2.0.

Analysis calculated for: C₂₅ H₃₄ F₃ N₃ O₅.0.5H₂ O: C, 57.46; H, 6.75; N,8.04. Found: C, 57.87; H, 6.24; N, 7.86.

EXAMPLE 493(RS)-1-[6-[(4-Hydroxycarbonylphenyl)aminocarbonylamino]-1-oxohexyl-N-[3-(1,1,1-trifluoro-4-methyl-2oxopentyl)]-L-prolinamide (Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═4-(HOCO)φNHCONH(CH₂)₅,A═CO, n=1)

Using the method of Example 14, the product of Example 47b was convertedinto the title product in 38% yield; HPLC, t_(R) =6.24 & 8.0, Col. A, H₂O:CH₃ CN (75:25), FR=2.0.

Analysis calculated for: C₂₅ H₃₃ F₃ N₄ O₆.2.5H₂ O: C, 51.1; H, 6.50; N,9.50. Found: C, 51.34; H, 5.93; N, 8.95.

EXAMPLE 503(RS)-1-(6-Phenylsulfonylamino-1-oxohexyl)-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φS(O₂)NH(CH₂)₅, A═CO, n=1) a.2(RS),3(SR)-1-[6-(Phenylmethoxycarbonylamino)-1-oxohexyl]-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ OCONH(CH₂)₅, A═CO, n=1)

DCC (6.35 g, 30.8 mmol) was added to a stirred solution ofN-CBZ-aminocaproic acid (6.84 g, 25.7 mmol), material prepared by themethod of Example 2b (6.89 g, 25.7 mmol), HOBT (6.94 g, 51.4 mmol) anddry THF (250 ml) at 0° C. under nitrogen. The resulting reaction mixturewas stirred at 0° C. for 1 hr, was allowed to warm to room temperature,and was stirred overnight before it was filtered. The filtrate wasconcentrated under vacuum to a brown residue which was dissolved inCHCl₃, and the CHCl₃ solution was washed (20% citric acid solution),dried (Na₂ SO₄), filtered, and concentrated under vacuum. The residuewas purified by flash chromatography (CHCl₃ :MeOH (97:3)) to give 8.0 g(61%) of the title compound as a waxy solid; TLC, R_(f) =0.35, CHCl₃:MeOH (95:5).

b.2(RS),3(SR)-1-(6-Amino-1-oxohexyl)-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═H₂ N(CH₂)₅, A═CO, n=1).

A mixture of the product of Example 50a (2.06 g, 3.99 mmol), EtOH (100ml), and 10% Pd/C (0.3 g) was placed on a Parr® shaker under 310,344.8Pascals (45 psi) of H₂ for 3 hr. The mixture was filtered throughCelite® and the Celite® cake was washed with EtOH. The EtOH washes andthe above filtrate were combined and concentrated under vacuum to give1.36 g (86%) of the title compound as a pale green waxy oil; TLC, R_(f)=0.2, CHCl₃ :MeOH (85:15).

c.2(RS),3(SR)-1-(6-Phenylsulfonylamino-1-oxohexyl)-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa R¹ ═CH(CH₃)CH₃, R³ ═φS(O₂)NH(CH₂)₅, A═CO, n=1)

Benzenesulfonyl chloride (0.6 g, 1.5 mmol) was added to a stirredsolution of the product of Example 50b (0.26 g, 1.5 mmol), TEA (0.3 g,3.0 mmol), and dry DMF (20 ml) under nitrogen at room temperature andthe resulting mixture was stirred at room temperature overnight. The DMFwas removed under vacuum to leave a brownish residue which was dissolvedin EtOAc. The EtOAc solution was washed (1N HCl), dried (MgSO₄), andfiltered. The filtrate was concentrated under vacuum to a residue whichwas purified by flash chromatography (CHCl₃ :MeOH (97:3)) to give 0.48 g(60%) of the title compound as a white powder; TLC, R_(f) =0.30 & 0.40,CHCl₃ :MeOH (95:5).

d.3(RS)-1-(6-Phenylsulfonylamino-1-oxohexyl)-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ia, R¹ ═CH(CH₃)CH₃, R³ ═φS(O₂)NH(CH₂)₅, A═CO, n=1)

Using the method of Example 8b, the product of Example 50c was oxidizedto afford, after purification by flash chromatography (Et₂ O:hexane(3:1) followed by a second column using CHCl₃ :MeOH (97:3)), the titleproduct (36%); HPLC, t_(R) =8.48 & 10.33, CH₃ CN: H₂ O (35:65), FR=2.0.

EXAMPLE 513(RS)-(1-Naphthylcarbonyl)-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═1-naphthyl, R⁴ ═H, A═CO,n=1) a.2(RS),3(SR)-(1-Naphthylcarbonyl)-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═1-naphthyl, R⁴ ═H,A═CO, n=1)

According to the method of Example 20a, material prepared by theprocedure of Example 3d was allowed to react with1-naphthalenecarbonylchloride to provide the title compound, isolated in38% yield after purification by preparative TLC (hexane:Et₂ O (4:6));TLC, R_(f) =0.46 & 0.41, MeOH:CHCl₃ (5:95).

Analysis calculated for: C₂₇ H₃₂ F₃ N₃ O₄ : C, 60.32; H, 6.37; N, 7.82.Found: C, 60.89; H, 6.21; N, 7.68.

b.3(RS)-(1-Naphthylcarbonyl)-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═1-naphthyl, R⁴ ═H, A═CO,n=1)

A solution of DMSO (29.7 g, 380 mmol) in CH₂ Cl₂ (81 ml) was addedslowly to a precooled solution (-43°) of oxalyl chloride (24.0 g, 190mmol) in CH₂ Cl₂ (350 ml), and the resulting solution was stirred for 15min before a solution of the product of Example 51b (9.4 mmol) in CH₂Cl₂ (83 ml) was added. After the reaction had been stirred 1 hr at -30°,diisopropylethylamine (48.9 g, 380 mmol) was added dropwise; and thereaction mixture was allowed to warm to room temperature before it waswashed (1N HCl, 5% aq NaOCl, brine), dried (Na₂ SO₄), filtered, andconcentrated under vacuum. The residue was purified by preparative TLC(hexane:Et₂ O (40:60)) to afford the title product (38%); HPLC, t_(R)=5.21 & 7.31, Col. A, CH₃ CN:H₂ O:TFA (50:50:0.1), FR= 1.5.

Analysis calculated for: C₂₇ H₃₂ F₃ N₃ O₄.0.75H₂ O: C, 60.32; H, 6.37;N, 7.82. Found: C, 60.69; H, 6.21; N, 7.68.

EXAMPLE 523(RS)-[4-(Methylsulfonylaminocarbonyl)phenylaminocarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═4-[CH₃ S(O₂)NHCO]φ, R⁴═H, A═NHCO, n=1)

Using the method of Example 89, material prepared according to theprocedure of Example 16 was allowed to react with methane sulfonamide toprovide, after purification by flash chromatography over Baker pH 5.0silica gel (gradient, CHCl₃ :MeOH (97:3) to (90:10)), the title product(59%), HPLC, t_(R) =2.60 & 3.33, Col C, H₂ O:CH₃ CN (60:40), FR=6.0.

Analysis calculated for: C₂₅ H₃₄ F₃ N₅ O₇ S.0.5H₂ O: C, 48.85; H, 5.74;N, 11.39. Found: C, 49.03; H, 5.74; N, 10.86.

EXAMPLE 533(RS)-[2-(4-Morpholinyl)ethoxycarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula 1b , R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═4-morpholinyl-CH₂ CH₂,R⁴ ═H, A═OCO, n=1) a.2(RS),3(SR)-[2-(4-Morpholinyl)ethoxycarbonyl]-L-valyl-N-[3-(1,1,1,-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide (Formula VIIb, R¹ ═CH(CH₃)CH₃, R²═CH(CH₃)₂, R³ ═4-morpholinyl--CH₂ CH₂, R⁴ ═H, A═OCO, n=1)

Using the method of Example 7b, material prepared by the procedure ofExample 3d was allowed to react with material prepared by the procedureof Example 33a to provide the named compound, isolated in 55% yieldafter purification by flash chromatography (MeOH:CHCl₃ (2.5:97.5));HPLC, t_(R) =4.62 & 5.85, Col. A, CH₃ CN:H₂ O (1:1), FR=2.0.

Analysis calculated for: C₂₃ H₃₉ F₃ N₄ O₆.H₂ O: C, 50.91; H, 7.61; N,10.32. Found: C, 50.95; H, 7.20; N, 10.02.

b.3(RS)-[2-(4-Morpholinyl)ethoxycarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH)CH₃, R² ═CH(CH₃)₂, R³ ═4-Morpholinyl--CH₂ CH₂, R⁴═H, A═OCO, n=1)

A solution of DMSO (29.7 g, 380 mmol) in CH₂ Cl₂ (135 ml) was added to aprecooled (-43°) solution of oxalyl chloride (24.0 g, 190 mmol) in CH₂Cl₂ (350 ml) and the resulting solution was stirred for 15 min. before asolution of the product of Example 53a (9.4 mmol) in CH₂ Cl₂ (125 ml)was added. The reaction mixture was allowed to warm from -43° to -20° asit was stirred for one hour; then diisopropylethylamine (48.9 g, 380mmol) was added dropwise and the reaction mixture was allowed to warm toroom temperature before it was further diluted with CH₂ Cl₂, washed (aqNaOH of pH=10), dried (K₂ CO₃ /Na₂ SO₄) and concentrated under vacuum.The residue was purified by flash chromatography (MeOH:CHCl₃ (2:98)) toafford the title product (18%); HPLC, t_(R) =2.00 & 2.60, Col. A, H₂O:CH₃ CN (1:1), FR=2.0.

Analysis calculated for: C₂₃ H₃₇ F₃ N₄ O₆ 1.5H₂ O: C, 50.26; H, 7.34; N,10.19. Found: C, 50.49; H, 6.96; N, 9.96.

EXAMPLE 543(RS)-[(2,4-Dichlorophenyl)carbonyl)]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═2,4-dichloroφ, R⁴ ═H A═CO,n=1) a.2(RS),3(SR)-[(2,4-Dichlorophenyl)carbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃) CH₃, R² ═CH(CH₃)₂, R³ ═2,4-dichloroφ, R⁴ ═H,A═CO, n=1)

Using the method of Example 20a, material prepared by the procedure ofExample 3d was allowed to react with 2,4-dichlorobenzoyl chloride toprovide the title compound, isolated in 98% yield; TLC, R_(f) =0.54,MeOH:CHCl₃ (5:95).

b.3(RS)-[(2,4-Dichlorophenyl)carbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═2,4-dichloroφ, R⁴ ═H,A═CO, n=1)

A solution of DMSO (29.7 g, 380 mmol) in CH₂ Cl₂ (27 ml) was addedslowly to a precooled (-65°) solution of oxalyl chloride (24.0 g, 190mmol) in CH₂ Cl₂ (350 ml), and the resulting solution was stirred for 15min before a solution of the product prepared by the method of Example54a (9.4 mmol) in CH₂ Cl₂ (250 ml) was added. After the reaction hadbeen stirred for 1 hr at -65°, diisopropylethylamine (48.9 g, 380 mmol)was added dropwise; and the reaction mixture was allowed to warm to roomtemperature before it was washed (1N HCl, brine), dried (Na₂ SO₄),filtered and concentrated under vacuum. The residue was purified byflash chromatography (MeOH:CHCl₃ (3:97)) to afford the title product(15%); HPLC, t_(R) =17.93 & 18.55 , Col. A, H₂ O:CH₃ CN (55:45 ),FR=2.0.

Analysis calculated for: C₂₃ H₂₈ Cl₂ F₃ N₃ O₄.H₂ O: C, 49.65; H, 5.43;N, 7.55. Found: C, 49.95; H, 5.31; N, 7.35.

EXAMPLE 553(RS)-Phenoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═φ, R⁴ ═H, A═OCO, n=1) a.2(RS),3(SR)-Phenoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═φ, R⁴ ═H, A═OCO, n=1)

Using the method of Example 20a, material prepared by the procedure ofExample 3d was allowed to react with phenyl chloroformate to provide thetitle compound, isolated in 61% yield after purification by flashchromatography (MeOH:CHCl₃ (5:95)); TLC, R_(f) =0.31 & 0.36, MeOH:CHCl₃(3:97).

b.3(RS)-Phenoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═φ, R⁴ ═H, A═OCO, n=1)

Using the method of Example 54b, the product of Example 55a was oxidizedto afford, after purification by flash chromatography (hexane:Et₂ O(15:85)), the title product (37%); HPLC, t_(R) =2.72 & 3.55, Col A, H₂O:CH₃ CN (1:1), FR=2.0.

Analysis calculated for: C₂₃ H₃₀ F₃ N₃ O₅.0.5H₂ O: C, 55.86; H, 6.32; N,8.50. Found: C, 56.07; H, 6.30; N, 8.48.

EXAMPLE 563(RS)-[2-(2-Pyridyl)ethoxycarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ 50 2-pyridyl-CH₂ CH₂, R⁴═H, A═OCO, n=1) a.2(RS),3(SR)-[2-(2-Pyridyl)ethoxycarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═2-pyridyl--CH₂ CH₂, R⁴═H, A═O, n=1)

Using the method of Example 34b, material prepared by the procedure ofExample 3d was allowed to react with material prepared by the procedureof Example 34a to provide the named compound, isolated in 50% yieldafter purification by flash chromatography (MeOH:CHCl₃ (4:96)); TLC,R_(f) =0.30 & 0.34, CHCl₃ :MeOH (95:5)

b.3(RS)-[2-(2-Pyridyl)ethoxycarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═2-pyridyl--CH₂ CH₂, R⁴═H, A═OCO, n=1)

Using the method of Example 54b, with omission of the acid wash, theproduct of Example 56a was oxidized to afford, after purification byflash chromatography twice (hexane:Et₂ O (1:1), then MeOH: CHCl₃(5:95)), the title product (19%); HPLC, t_(R) =9.52 & 14.58, Col.A, H₂O:CH₃ CN (60:40), FR=1.0.

Analysis calculated for: C₂₄ H₃₃ F₃ N₄ O₅.0.75H₂ O: C, 54.59; H, 6.58;N, 10.61. Found: C, 54.63; H, 6.47; N, 10.55.

EXAMPLE 573(RS)-[(4-Fluorophenyl)aminocarbonyl)]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═4-Fφ R⁴ ═H, A═NHCO, n=1)a.2(RS),3(SR)-[(4-Fluorophenyl)aminocarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH (CH₃)₂, R³ ═4-Fφ, R⁴ ═H A═NHCOn=1)

Using the method of Example 15a, material prepared by the procedure ofExample 3d was allowed to react with 4-fluorophenylisocyanate to providethe title compound, isolated in 84% yield after purification by flashchromatography (gradient, MeOH:CHCl₃ (2.5:97.5) to (5:95)); TLC, R_(f)=0.37, MeOH:CHCl₃ (5:95)

b.3(RS)-[(4-Fluorophenyl)aminocarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═4-Fφ, R⁴ ═H, A═NHCO, n=1)

Using the method of Example 54b, the product of Example 57a was oxidizedto afford, after purification by flash chromatography (MeOH:CHCl₃(3:97)) the title product (42%); HPLC, t_(R) =8.87 & 12.10, Col A, H₂O:CH₃ CN (60:40), FR=1.0.

Analysis calculated for: C₂₃ H₃₀ F₄ N₄ O₄ : C, 54.97; H, 6.02; N, 11.15.Found: C, 55.18; H, 6.15; N, 11.08.

EXAMPLE 583(RS)-[4-(Phenylsulfonylaminocarbonyl)phenylaminocarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂ R³ ═4-[φS(O₂)NHCO]φ, R⁴ ═H,A═NHCO, n=1)

Using the method of Example 89, material prepared according to theprocedure of Example 16 was allowed to react with benzene sulfonamide toprovide, after purification by flash chromatography on Baker pH 5.0silica gel (CHCl₃ :MeOH (97:3)), the title product (42%); HPLC, t_(R)=4.05 & 5.93, Col C, H₂ O:CH₃ CN (60:40), FR=6.0.

Analysis calculated for: C₃₀ H₃₆ F₃ N₅ O₇.0.5H₂ O: C, 53.25; H, 5.51; N,10.34. Found: C, 53.38; H, 5.61; N, 10.02.

EXAMPLE 593(RS)-[2-(3-Thiophenyl)ethoxycarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂ R³ =3-thiophenyl-CH₂ CH₂, R⁴═H, A═OCO, n=1) a. 4-Nitrophenyl 2-(3-thiophenyl)ethyl carbonate

Using the method of Example 7a, 3-thiopheneethanol was treated with4-nitrophenyl chloroformate to afford, after purification by flashchromatography (EtOAc:hexane (1:9)), the title product (56%); TLC, R_(f)=0.25, EtOAc:hexane (1:9).

b.2(RS),3(SR)-[2-(3-Thiophenyl)ethoxycarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═3-thiophenyl--CH₂ CH₂,R⁴ ═H, A═0, n=1)

Using the method of Example 7b, material prepared by the procedure ofExample 3d was allowed to react with the product of Example 59a toprovide the title compound, isolated in 58% yield after purfication byflash chromatography (acetone: hexane (3:7)); TLC, R_(f) =0.23 & 0.27,MeOH:CHCl₃ (5:95).

Analysis calculated for: C₂₄ H₃₄ F₃ N₃ O₅ S: C, 52.96; H, 6.57; N, 8.06.Found: C, 53.28; H, 6.46; N, 7.77.

c.3(RS)-[2-(3-Thiophenyl)ethoxycarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═3-thiophenyl--CH₂ CH₂ ,R⁴ ═H, A═OCO, n=1)

A solution of DMSO (29.7 g, 380 mmol) in CH₂ Cl₂ (135 ml) was addedslowly to a precooled (-43°) solution of oxalyl chloride (24.0 g, 190mmol) in CH₂ Cl₂ (350 ml). The resulting solution was stirred 15 minbefore a solution of material prepared by the method of Example 59b (9.4mmol) in CH₂ Cl₂ (125 ml) was added and the reaction was stirred at -43°for an additional hour. Diisopropylethylamine (48.9 g, 380 mmol) wasadded dropwise, and the reaction mixture was allowed to warm to roomtemperature before it was washed (1N aq HCl, 5% aq NaOCl, brine), dried(Na₂ SO₄), filtered, and concentrated under vacuum. Purification of theresidue by flash chromatography (acetone:hexane (1:4)) afforded thetitle product (23%); HPLC, t_(R) =5.09 & 7.61, Col A, H₂ O:CH₃ CN (1:1),FR=2.0.

Analysis calculated for: C₂₄ H₃₂ F₃ N₃ O₅ S: C, 53.17; H, 6.21; N, 8.09.Found: C, 52.92; H, 6.26; N, 8.09.

EXAMPLE 60 3(RS)-(1,1-Dimethylethoxycarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═CH₃ C(CH₉)₉, R⁴ ═H, A═OCO,n=1) a.2(RS),3(SR)-(1,1-Dimethylethoxycarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═CH₃ C(CH₃)₂, R⁴ ═H,A═OCO, n=1)

DCC (5.90 g, 28.7 mmol) was added to a stirred solution of HOBT (7.76 g,57.4 mmol), BOC-α-aminobutanoic acid (5.60 g, 27.4 mmol), and materialprepared by the procedure of Example 2b (7.00 g, 26.1 mmol) in dry THF(130 ml) at 0° under nitrogen. After the resulting reaction mixture hadbeen stirred at 0° for 1 hr, it was allowed to warm to room temperatureand was stirred overnight. The reaction mixture was filtered; and thefiltrate was concentrated under vacuum to a residue which wasredissolved in EtOAc. The resulting solution was washed satd NaHCO₃brine), dried (Na₂ SO₄), filtered, and concentrated under vacuum to aresidue which was purified by flash chromatography (EtOAc:CH₂ Cl₂ (1:3))to give the title compound (95%); TLC, R_(f) =0.29, EtOAc:CH₂ Cl₂ (3:7).

b.3(RS)-(1,1-Dimethylethoxycarbonyl)-L-e-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═CH₃ C(CH₃)₂, R⁴ ═H, A═OCO,n=1)

Using the method of Example 61c the product of Example 60a was oxidizedto afford, after purification by flash chromatography (MeOH:CHCl₃(1.5:98.5), the title product (47%); HPLC, t_(R) =10.21 & 14.54, Col A,H₂ O:CH₃ CN (65:35), FR=2.0.

Analysis calculated for: C₂₀ H₃₂ F₃ N₃ O₅ : C, 53.21; H, 7.14; N, 9.31.Found: C, 53.65; H, 7.21; N, 9.51.

EXAMPLE 61 3(RS)-[1-Oxo-2-(2-thiophenyl)ethyl]-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═(2-thiophenyl)CH₂, R⁴ ═H,A═CO, n=1) a.2(RS),3(SR)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamidetrifluoroacetic acid salt (Formula IVb, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R⁴═H, n=1)

A solution of material prepared by the procedure of Example 60a (4.0 g,8.84 mmol) and TFA (32 ml, 415 mmol) in CH₂ Cl₂ (32 ml) was stirred atroom temperature for 22 hr before the solvents were removed underreduced pressure to afford the crude product (5 g, >100%) as a colorlessglass which was used without further purification or characterization.

b.2(RS),3(SR)-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═(2-thiophenyl)CH₂, R⁴═H, A═CO, n=1)

DCC (0.315 g, 1.53 mmol) was added to a stirred solution of HOBT (0.413g, 3.06 mmol) 2-thiopheneacetic acid (0.222 g, 1.53 mmol), NMM (0.154 g,1.53 mmol), and material prepared according to Example 61a (0.650 g,1.39 mmol) in dry THF (20 ml) at 0° under nitrogen. After the resultingreaction mixture had been stirred at 0° for 1 hr, it was allowed to warmto room temperature and was stirred overnight. The reaction mixture wasfiltered; and the filtrate was concentrated under vacuum to a residuewhich was dissolved in EtOAc. The resulting solution was washed (brine),dried (Na₂ SO₄), filtered, and concentrated under vacuum to a residuewhich was purified by flash chromatography (acetone:hexane (1:1)) togive of the title compound (33%); TLC, R_(f) =0.40 & 0.44, MeOH:CHCl₃(1:9).

Analysis calculated for: C₂₁ H₃₀ F₃ N₃ O₄ S: C, 52.82; H, 6.33; N, 8.80.Found: C, 52.43; H, 6.53; N, 8.08.

c. 3(RS)-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═(2-thiophenyl)CH₂, R⁴ ═H,A═C₀, n=1)

To a suspension of CRO₃ (0.84 g, 8.4 mmol) in dry CH₂ Cl₂ (50 ml) wasadded dry pyridine (1.36 ml, 17 mmol), and the mixture stirred at roomtemperature for 30 min. To the resulting burgundy colored suspension wasadded 1 g of Celite® followed by the product from Example 61b (0.20 g,0.42 mmol) in CH₂ Cl₂ (5 ml). The mixture was stirred until TLCindicated all the alcohol was consumed. The mixture was then filteredthrough a pad of silica gel with methanol:chloroform (1:9) and thesolvents removed from the filtrate under vacuum. The crude product waspurified by preparative TLC (MeOH:CHCl₃ (5:95)) to afford the product(150 mg) as a white solid; HPLC, t_(R) =4.18 & 5.65, Col A, H₂ O: CH₃ CN(60:40), FR=2.0.

Analysis calculated for: C₂₁ H₂₈ F₃ N₃ O₄ S.O.5H₂ O: C, 52.06; H, 6.03;N, 8.67. Found: C, 52.03; H, 6.19; N, 8.38.

EXAMPLE 623(RS)-(Phenylmethoxycarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═φCH₂, R⁴ ═H, A═OCO, n=1)a.2(RS),3(SR)-(Phenylmethoxycarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═φCH₂, R⁴ ═H, A═OCO, n=1)

Using the method of Example 20a, material prepared according to theprocedure of Example 61a was allowed to react with 1.5 equivalents ofbenzyl chloroformate in one-fourth the amount of CHCl₃ used in themethod of Example 20a to produce the title compound, isolated in 51%yield after purification by flash chromatography (acetone:hexane (1:4));TLC, R_(f) =0.38 & 0.43, acetone:hexane (40:60).

b.3(RS)-(Phenylmethoxycarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═φCH₂, R⁴ ═H, A═OCO, n=1)

Using the method of Example 61c the product of Example 62a was oxidizedto afford, after purification by flash chromatography (acetone: hexane(30:70)), the title product (64%); HPLC, t_(R) =5.69 & 7.75, Col A, H₂O:CH₃ CN (55:45), FR=2.0.

Analysis calculated for: C₂₃ H₃₀ F₃ N₃ O₅.0.80H₂ O: C, 55.26; H, 6.37;N, 8.40. Found: C, 55.10; H, 6.19; N, 8.77.

EXAMPLE 63 3(RS)-(Phenoxycarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═φ, R⁴ ═H, A═OCO, n=1) a.2(RS),3(SR)-(Phenoxycarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═φ, R⁴ ═H, A═OCO, n=1)

Using the method of Example 20a, but using NMM instead of TEA, materialprepared according to the procedure of Example 61a was allowed to reactwith 1.5 equivalents of phenyl chloroformate to produce the titlecompound, isolated in 18% yield after purification by preparative TLC(acetone:hexane (3:7)); TLC, R_(f) =0.32 & 0.37, acetone:hexane (3:7).

b.3(RS)-(Phenoxycarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═φ, R⁴ ═H, A═OCO, n=1)

Using the method of Example 61c, the product of Example 63a was oxidizedto afford, after purification by flash chromatography (EtOAc: hexane(1:9)), the title product (60%); HPLC, t_(R) =4.57 & 6.51, Col A, H₂O:CH₃ CN (55:45).

Analysis calculated for: C₂₂ H₂₈ F₃ N₃ O₅ : C, 56.04; H, 5.98; N, 8.90.Found: C, 56.04; H, 6.18; N, 8.85.

EXAMPLE 643(RS)-[4-(1-Oxoethylamino)phenylsulfonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═4--(CH₃ CONH)φ, R⁴ ═H,A═S(O₂), n=1) a.2(RS),3(SR)-[4-(1-Oxoethylamino)phenylsufonyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═4-(CH₃ CONH)φ, R⁴ ═H,A═S(O₂), n=1)

To a stirred solution of material prepared according to Example 3d (1.00g, 2.72 mmol) and NMM (0.28 g, 0.30 ml, 2.80 mmol) in CH₂ Cl₂ (50 ml)under N₂ was added 4-acetamidobenzenesulfonyl chloride (0.64 g, 2.72mmol). After stirring the reaction mixture overnight at roomtemperature, the solution was washed (5% aq citric acid, brine), dried(Na₂ SO₄), filtered, and concentrated to leave an orange syrup which wasflash chromatagraphed over silica gel (350 g) (MeOH: CHCl₃ (7:93)) togive the title product (810 mg, 52.60%); TLC, R_(f) =0.34 & 0.45,MeOH:CHCl₃ (7:93).

b.3(RS)-[4-(1-Oxoethylamino)phenylsufonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R₂ ═CH(CH₃)CH₃, R³ ═4-(CH₃ CONH)φ, R⁴ ═H,A═S(O₂), n=1)

Using the method of Example 31c, the product of Example 64a was oxidizedto afford, after purification by flash chromatography (MeOH:CHCl₃(5:95)), the title product (84%); HPLC, t_(R) =3.22 & 4.58, Col A, CH₃CN:H₂ O (40:60), FR=2.0.

Analysis calculated for: C₂₄ H₃₃ F₃ N₄ O₆ S.H₂ O: C, 49.65; H, 6.08; N,9.65. Found: C, 49.73; H, 5.86; N, 9.53.

EXAMPLE 65 3(RS)-N²⁻ (1,1-Dimethylethoxycarbonyl)-N⁶-phenylmethoxycarbonyl-L-lysyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═φCH₂ OCONH(CH₂)₄, R³ ═(CH₃)₃ C, R⁴ ═H,A═OCO, n=1) a. 2(RS),3(SR)-N² -(1,1-Dimethylethoxycarbonyl)-N⁶-phenylmethoxycarbonyl-L-lysyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═φCH₂ OCONH(CH₂)₄, R³ ═(CH₃)₃ C, R⁴═H, A═OCO, n=1)

Using the method of Example 84b, N² -BOC-N⁶ -CBZ-L-lysine was allowed toreact with material prepared by the method of Example 2b to provide,after purification by flash chromatography (gradient elution, MeOH:CHCl₃(2.5:97.5) to (5:95)), the title product (73%); TLC, R_(f) =0.57,MeOH:CHCl₃ (5:95).

b. 3(RS)-N² -(1,1-Dimethylethoxycarbonyl)-N⁶-phenylmethoxycarbonyl-L-lysyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═φCH₂ OCONH(CH₂)₄, R³ ═(CH₃)₃ C, R⁴ ═H,A═OCO, n=1)

Using the method of Example 31c, the product of Example 65a was oxidizedto afford, after purification by flash chromatography (gradient elution,MeOH: CHCl₃ (2.5:97.5) to (5:95)), the title product (65%); HPLC, t_(R)=4.15 & 5.14, Col A, H₂ O:CH₃ CN (45:55), FR=2.0.

Analysis calculated for: C₃₀ H₄₃ F₃ N₄ O₇.0.5H₂ O: C, 56.51; H, 6.95; N,8.79. Found: C, 56.45; H, 6.58; N, 8.42.

EXAMPLE 663(RS)-[(2-Amino-5-chlorophenyl)carbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂ --, R³ ═2-NH₂ -5-Cl-φ, R⁴ ═H,A═CO, n=1) a.2(RS),3(SR)-[(2-Amino-5-chlorophenyl)carbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═2--NH₂ -5-Cl-φ, R⁴ ═H,A═CO, n=1)

A solution of material prepared according to Example 3d (1 g, 2.7 mmol)in CH₂ Cl₂ (50 ml) was treated with 5-chloroisotoic anhydride (0.54 g,2.7 mmol) at room temperature and the mixture was stirred overnightbefore it was washed (5% aqueous NaHCO₃, brine), dried (Na₂ SO₄),concentrated under vacuum, and purified by flash chromatography(MeOH:CHCl₃ (3:97)) to give the title product (1.4 g, 78%) as a whitefoam; TLC, R_(f) =0.30 & 0.25, MeOH:CHCl₃ (5:95).

b.3(RS)-[(2-Amino-5-chlorophenyl)carbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)₂, R³ ═2-NH₂ -5-Cl-φ, R⁴ ═H,A═CO, n=1)

Using the method of Example 31c, the product of Example 66a was oxidizedto afford, after purification by flash chromatography (MeOH:CHCl₃(3:97)), the title product (76%); HPLC, t_(R) =3.41 & 4.62, Col A, H₂O:CH₃ CN (50:50), FR=2.0.

Analysis calculated for: C₂₃ H₃₀ F₃ N₄ O₄.H₂ O: C, 51.45; H, 6.01; N,10.43. Found: C, 51.65; H, 5.74; N, 9.68.

EXAMPLE 673(RS)-(4-Methoxyphenylcarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₂ CH₃, R³ ═4-(CH₃₀)--φ, R⁴ ═H, A═CO,n=1) a.2(RS),3(SR)-(4-Methoxyphenylcarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂, R³ ═4-(CH₃ O)--φ, R⁴ ═H,A═CO, n=1)

Using the method of Example 20a, material prepared according to theprocedure of Example 61a was allowed to react with4-methoxybenzoylchloride to provide the title compound, isolated in 34%yield after purification by flash chromatography (EtOAc:hexane (60:40)),TLC, R_(f) =0.71 & 0.73, MeOH:CHCl₃ (1:9).

Analysis calculated for: C₂₃ H₃₂ F₃ N₃ O₅.0.3H₂ O: C, 56.04; H, 6.67; N,8.52. Found: C, 56.06; H, 6.60; N, 8.14.

b.3(RS)-(4-Methoxyphenylcarbonyl)-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂, R³ ═4-(CH₃ O)--φ, R⁴ ═H, A═CO,n=1).

Using the method of Example 61c, except the alcohol was dissolved infive times the solvent, the product of Example 67a was oxidized toafford, after purification by preparative TLC (MeOH: CHCl₃ (1:9)), thetitle product (40%); HPLC, t_(R) =8.89 & 11.75, Col A, H₂ O:CH₃ CN(70:30), FR=2.0.

Analysis calculated for: C₂₃ H₃₀ F₃ N₃ O₅.H₂ O: C, 54.86; H, 6.41; N,8.35. Found: C, 54.89; H, 6.38; N, 7.48.

EXAMPLE 68 3(RS)-[2-(Tricylo[3.3.1.1³,7]-dec-1-yl)ethoxycarbonyl]-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═(1-adamantyl)-CH₂ CH₂,R⁴ ═H, A═OCO, n=1) a. 2(RS),3(SR)-[2-(Tricylco[3.3.1.1³,7]-dec-1-yl)ethoxycarbonyl]-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂, R³ ═(1-adamantyl)-CH₂ CH₂,R⁴ ═H, A═OCO, n=1)

Using the method of Example 34b, material prepared according to theprocedure of Example 61a was allowed to react with material preparedaccording to Example 7a to provide the title compound, isolated in 42%yield after purification by flash chromatography (EtOAc:hexane (20:80),then (50:50)); TLC, R_(f) =0.33 & 0.44, MeOH:CHCl₃ (5.95).

b. 3(RS)-[2-(Tricyclo[3.3.1.1³,7]-dec-1-yl)ethoxycarbonyl]-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂, R³ ═(1-adamantyl)-CH₂ CH₂, R⁴═H, A═OCO, n=1)

Using the method of Example 61c, the product of Example 68a was oxidizedto afford, after purification by flash chromatography (Et₂ O:hexane(50:50), then (90:10)), the title product (66%); HPLC, t_(R) =4.64 &5.63, Col A, H₂ O:CH₃ CN (25:75), FR=2.0.

Analysis calculated for: C₂₈ H₄₂ F₃ N₃ O₅.0.15H₂ O: C, 60.01; H, 7.60.Found: C, 59.76; H, 7.65.

EXAMPLE 69 3(RS)-N² -(1,1-Dimethylethoxycarbonyl)-N⁶-phenylsulfonyl-L-lysyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═φS(O₂)NH(CH₂)₄, R³ ═(CH₃)₃ C, R⁴ ═H,A═OCO, n=1) a. 2(RS),3(SR)-N²-(1,1-Dimethylethoxycarbonyl)-L-lysyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═H₂ N(CH₂)₄ R³ ═(CH₃)₃ C, R⁴ ═H,A═OCO, n=1)

To a solution of material prepared according to Example 65a (3.0 g, 4.8mmol) in absolute EtOH (60 ml) was added 10% Pd on carbon (0.6 g). Theresulting suspension was stirred overnight under an atmosphere (102,325Pascals) of H₂. Additional 10% Pd on carbon (0.3 g) was added, andstirring was continued for several hours. The reaction was filteredthrough Celite® and concentrated under vacuum to give the product (2.48g), which was used directly.

b. 2(RS),3(SR)-N² -(1,1-Dimethylethoxycarbonyl)-N⁶-phenylsulfonyl-L-lysyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═φS(O₂)NH(CH₂)₄, R³ ═(CH₃)₃ C, R⁴ ═H,A═OCO, n=1)

Using the method of Example 72b, except NMM was used instead of TEA, theproduct of Example 69a was treated with benzene sulfonyl chloride toproduce the title product, purified by flash chromatography (CHCl₃ :MeOH(95:5)), in 69% yield; TLC, R_(f) =0.29, MeOH:CHCl₃ (95:5).

c. 3(RS)-N² -(1,1-Dimethylethoxycarbonyl)-N⁶-phenylsulfonyl-L-lysyl-N-[3-(1,1,1-trifluoro-4-methyl-2oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═φS(O₂)NH(CH₂)₄, R³ ═(CH₃)₃ C, R⁴ ═H,A═OCO, n=1)

Using the method of Example 31c, the product of Example 69b was oxidizedto afford, after purification by flash chromatography (gradient elution,MeOH:CHCl₃ (0:100) to (2.5:97.5)), the title product (57%); HPLC, t_(R)=7.48 & 9.11, Col A, CH₃ CN:H₂ O (1:1), FR=1.0.

Analysis calculated for: C₂₈ H₁₆ F₃ N₄ O₇ S.H₂ O: C, 51.52; H, 6.64; N,8.58. Found: C, 51.47; H, 6.46; N, 7.80.

EXAMPLE 703(RS)-(4-Ethoxycarbonylphenyl)aminocarbonyl-L-α-aminobutanoyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂, R³ ═4-[CH₃ CH₂ OC(O)]φ, R⁴ ═H,A═NHCO, n=1) a.2(RS),3(SR)-(4-Ethoxycarbonylphenyl)aminocarbonyl-L-α-aminobutyroyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂, R³ ═4-[CH₃ CH₂ OC(O)]φ, R⁴═H, A═NHCO, n=1)

Using the method of Example 15a, material prepared according to theprocedure of Example 61a was allowed to react with ethyl4-iso-cyanatobenzoate to provide the title compound, isolated in 46%yield; TLC, R_(f) =0.53, MeOH:CHCl₃ (5:95).

b.3(RS)-(4-Ethoxycarbonylphenyl)aminocarbonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂, R³ ═4-[CH₃ CH₂ OC(O)]φ, R⁴ ═H,A═NHCO, n=1)

Using the method of Example 61c, the product of Example 70a was oxidizedto afford, after purification by flash chromatography (CHCl₃ : MeOH(97:3)), the title product (68%); HPLC, t_(R) =6.35 & 8.70, Col A, H₂ O:CH₃ CN (60:40), FR=2.0.

Analysis calculated for: C₂₅ H₃₃ F₃ N₄ O₆.0.5H₂ O: C, 54.44; H, 6.21; N,10.15. Found: C, 54.76; H, 6.13; N, 10.27.

EXAMPLE 713(RS)-(4-Hydroxycarbonylphenyl)aminocarbonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂, R³ ═4[HOC(O)]φ, R⁴ ═H, A═NHCO,n=1)

Using the method of Example 14, material prepared according to theprocedure of Example 70b was converted into the title product andisolated by flash chromatography on Baker pH 5.0 silica gel (CHCl₃ :MeOH(97:3)) in 61% yield; HPLC, t_(R) =3.68 & 4.69, Col A, H₂ O:CH₃ CN(3:1), FR=2.0.

Analysis calculated for: C₂₃ H₂₉ F₃ N₄ O₆.H₂ O: C, 51.88; H, 5.86; N,10.52. Found: C, 51.98; H, 5.69; N, 10.19.

EXAMPLE 72 3(RS)-N⁶ -Phenylmethoxycarbonyl-N²-phenylsulfonyl-L-lysyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₂)₄ NHCOOCH₂ φ, R³ ═φ, R⁴ ═H,A═S(O₂), n=1) a. 2(RS),3(SR)-N-Phenylmethoxycarbonyl-L-lysyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamidetrifluoroacetic acid salt (Formula IVb, R¹ ═CH(CH₃)CH₃, R² ═φCH₂OCONH(CH₂)₄ --, R⁴ ═H, n=1)

To a solution of product prepared according to the procedure of Example65a (2.75 g, 4.4 mmol) in CH₂ Cl₂ (7 ml) was added TFA (10.4 g, 90mmol), and the solution was stirred at room temperature for 1 hr.Toluene (10 ml) was added, and the reaction mixture was concentratedunder vacuum to afford the title product (3.4 g) which was used withoutfurther purification.

b. 2(RS),3(SR)-N⁶ -Phenylmethoxycarbonyl-N²-phenylsulfonyl-L-lysyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₂)₄ NHC(O)OCH₂ φ, R³ ═φ, R⁴ ═H,A═S(O₂), n=1)

To a solution of the product of Example 72a (0.83 g, 1.3 mmol) in CH₂Cl₂ (6.5 ml) were added TEA (0.39 g, 3.9 mmol) and benzenesulfonylchloride (0.25 g, 1.4 mmol), and the reaction mixture was stirredovernight at room temperature. After the reaction mixture wasconcentrated under vacuum, the residue was dissolved in EtOAc. The EtOAcsolution was filtered and concentrated under vacuum to a residue whichwas purified by flash chromatography (gradient elution, MeOH:CHCl₃(2.5:97.5) to (5:95)) to give the title product (81%); TLC, R_(f) =0.52,MeOH:CHCl₃ (5:95).

c. 3(RS)-N⁶ -Phenylmethoxycarbonyl-N²-phenylsulfonyl-L-lysyl-N-[3-(1,1,1,-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R₂ ═(CH₂)₄ NHC(O)OCH₂ φ, R³ ═φ, R⁴ ═H,A═S(O₂), n=1)

Using the method of Example 31c, the product of Example 72b was oxidizedto afford, after purification by flash chromatography (gradient elution,CHCl₃ to CHCl₃ :MeOH (97.5:2.5)), the title product (63%); HPLC, t_(R)=5.0 & 6.3, Col A, CH₃ CN:H₂ O (3:2), FR=1.0.

Analysis calculated for: C₃₁ H₃₉ F₃ N₄ O₇ S. H₂ O: C, 54.22; H, 6.02; N,8.16. Found: C, 54.17; H, 5.80; N, 7.86.

EXAMPLE 733(RS)-[2-(2-Methoxyethoxy)ethoxycarbonyl]-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═CH₃ O(CH₂)₂ O(CH₂)₂, R⁴═H, A═OCO n=1) a.2(RS),3(SR)-[2-(2-Methoxyethoxy)ethoxycarbonyl]-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═CH₃ O(CH₂)₂ O(CH₂)₂,R⁴ ═H, A═OCO, n=1)

Using the method of Example 34b, material prepared according to theprocedure of Example 61a was allowed to react with material preparedaccording to the procedure of Example 19a to provide the title compound,isolated in 75% yield after purification by flash chromatography(gradient, acetone:hexane (1:9) to (7:3)), TLC, R_(f) =0.30 & 0.35,acetone:hexane (40:60).

Analysis calculated for: C₁₇ H₂₉ F₃ N₂ O₆.0.5H₂ O: C, 48.22; H, 7.14; N,6.61. Found: C, 48.13; H, 6.90; N, 6.07.

b.3(RS)-[2-(2-Methoxyethoxy)ethoxycarbonyl]-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂, R³ ═CH₃ O(CH₂)₂, R⁴ ═H, A═OCO,n=1)

Using the method of Example 61c the product of Example 73a was oxidizedto afford, after purification by flash chromatography (gradient elution,EtOAc:hexane (1:1) to EtOAc to acetone:EtOAc (1:9)), the title product(40%); HPLC, t_(R) =5.70 & 8.95, Col A, H₂ O:CH₃ CN (75:25), FR=2.0.

Analysis calculated for: C₂₁ H₃₄ F₃ N₃ O₇ : C, 48.77; H, 7.14; N, 6.61.Found: C, 48.13; H, 6.90; N, 6.09.

EXAMPLE 743(RS)-[Z-(4-Aminocarbonylamino-1,4-dioxo-2-butenyl)]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ Z--H₂NC(O)NHC(O)CH═CH--, R⁴ ═H, A═CO, n=1) a.2(RS),3(SR)-[Z-(4-Aminocarbonylamino-1,4-dioxo-2-butenyl)]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═Z--H₂NC(O)NHC(O)CH═CH--, R⁴ ═H, A═CO, n=1)

Using the method of Example 21b, material prepared by the procedure ofExample 3d was allowed to react withZ-4-aminocarbonylamino-4-oxo-2-butenoic acid to provide the titlecompound, isolated in 26% yield after purification by flashchromatography (MeOH:CHCl₃ (5:95)); TLC, R_(f) =0.17 & 0.25, MeOH:CHCl₃(5:95).

b.3(RS)-[Z-(4-Aminocarbonylamino-1,4-dioxo-2-butenyl)]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═Z--H₂NC(O)NHC(O)CH═CH--, R⁴ ═H, A═CO, n=1)

Using the method of Example 31c, the product of Example 74a was oxidizedto afford, after purification by flash chromatography (MeOH:CHCl₃(4:96)), the title product (29%); HPLC, t_(R) =1.78 & 2.45, Col A, H₂O:CH₃ CN (65:35), FR=2.0.

Analysis calculated for: C₂₁ H₃₀ F₃ N₅ O₆.1.5H₂ O: C, 47.37; H, 6.25; N,13.15. Found: C, 47.29; H, 5.77; N, 13.02.

EXAMPLE 753(RS)-Phenylaminocarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═φ, R⁴ ═H, A═NHCO, n=1)a.2(RS),3(SR)-Phenylaminocarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═φ, R⁴ ═H, A═NHCO,n=1)

Using the method of Example 15a, material prepared by the procedure ofExample 3d was allowed to react with phenylisocyanate to provide thetitle compound, isolated in 62% yield after purification by flashchromatography (MeOH:CHCl₃ (2:98)); TLC, R_(f) =0.24 & 0.32, MeOH:CHCl₃(2:98).

b.3(RS)-Phenylaminocarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═φ, R⁴ ═H, A═NHCO, n=1)

Using the method of Example 31c, the product of Example 75a was oxidizedto afford, after purification by flash chromatography (MeOH:CHCl₃(2:98)), the title product (75%); HPLC, t_(R) =5.70 & 8.77, Col A, H₂O:CH₃ CN (60:40), FR=2.0.

Analysis calculated for: C₂₃ H₃₁ F₃ N₄ O₄.0.75H₂ O: C, 55.47; H, 6.58;N, 11.25. Found: C, 55.46; H, 6.50; N, 10.72.

EXAMPLE 763(RS)-(4-Ethoxycarbonylphenyl)aminocarbonyl-L-phenylalanyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═φCH₂ --, R³ ═4-[CH₃ CH₂ OC(O)]φ, R⁴ ═H,A═NHCO, n=1) a.2(RS),3(SR)-1-Phenylmethoxycarbonyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIa, R¹ ═CH(CH₃)CH₃, R³ ═φCH₂ --, A═OCO, n=1)

Using the method of Example 2a, material prepared according to themethod of Example 4 was allowed to react with CBZ-L-proline to providethe title compound (100%); TLC, R_(f) =0.37 & 0.45, MeOH: CH₂ Cl₂(5:95).

b.2(RS),3(SR)-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula IVa, R¹ ═CH(CH₃)CH₃, n=1)

Using the method of Example 2b, the product of Example 76a was convertedinto the title product (100%); TLC, R_(f) =0.73 & 0.81, MeOH:CH₂ Cl₂satd with NH₄ OH (15:85).

c.2(RS),3(SR)-Phenylmethoxycarbonyl-L-phenylalanyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₂ φ, R³ ═φCH₂ --, R⁴ ═H, A═OCO,n=1)

After DCC (2.27 g, 11.0 mmol) was added to a stirred solution ofCBZ-L-phenylalanine (2.29 g, 10.0 mmol), HOBT (2.70 g, 17.6 mmol) andmaterial prepared according to Example 76b (2.68 g, 10.0 mmol) in dryTHF (45 ml) chilled to -17° C., the mixture was left at room temperatureovernight, filtered, and concentrated to remove the THF before it wastaken up in Et₂ O and EtOAc. The resulting solution was washed (satdNaHCO₃ (2×), 1N HCl, brine), dried (MgSO₄), filtered, concentrated, andtaken up in minimal CH₂ Cl₂. After N,N'-dicyclohexylurea was filtered,the solution was concentrated under vacuum, and dried under vacuum toprovide the title compound in quantitative yield as a white foam; TLC,R_(f) =0.37 & 0.45, MeOH:CH₂ Cl₂ (5:95).

d.2(RS),3(SR)-L-Phenylalanyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula IVb, R¹ ═CH(CH₃)CH₃, R² ═CH₂ φ, R⁴ ═H, n=1)

A mixture of the product of Example 76c (501.3 mg, 0.898 mmol) and50%-water wet 10% Pd/C (50 mg) in absolute EtOH (17 ml) was stirredunder hydrogen (1 atmosphere, 101,325 Pascals) overnight, filtered,concentrated and dried under vacuum to provide the title compound inquantitative yield; TLC, R_(f) =0.14, MeOH: CH₂ Cl₂ (5:95); R_(f) =0.43& 0.48 MeOH: NH₄ OH satd CH₂ Cl₂ (5:95).

e.2(RS),3(SR)-(4-Ethoxycarbonylphenyl)aminocarbonyl-L-phenylalanyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═φCH₂ --, R³ ═4-[CH₃ CH₂ OC(O)]φ--, R⁴═H, A═NHCO, n=1)

Using the method of Example 15a material prepared by the procedure ofExample 76d was allowed to react with ethyl 4-isocyanatobenzoate toprovide the title compound, isolated in 95% yield; TLC; R_(f) =0.21 &0.26, MeOH:CH₂ Cl₂ (5:95).

f.3(RS)-(4-Ethoxycarbonylphenyl)aminocarbonyl-L-phenylalanyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₂ --, R³ ═4-[CH₃ CH₂ OC(O)]φ--, R⁴═H, A═NHCO, n=1)

Using the method of Example 61c, the product of Example 76e was oxidizedto afford, after purification by flash chromatography (gradient elution,Et₂ O: pentane (11:1) to Et₂ O), the title product (94%); HPLC, t_(R)=10.26 & 13.52, Col A, CH₃ CN:H₂ O (45:55), FR=2.0.

Analysis calculated for: C₃₀ H₃₅ F₃ N₄ O₆. 1.24H₂ O: C, 57.47; H, 6.03;N, 8.94. Found: C, 57.43; H, 6.02; N, 8.97.

EXAMPLE 773(RS)-[[4-[(1-Naphthylsulfonyl)aminocarbonyl]phenyl]aminocarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃) CH₃, R² ═(CH₃)₂ CH--, R³═4-[1-naphthyl-S(O₂)NHC(O)]φ, R⁴ ═H, A═NHCO, n=1) a. 1-Naphthalenesulfonamide

Ammonia was passed (for 5 min) into a stirred solution of1-naphthalenesulfonyl chloride (5.0 g, 22 mmol) and anhydrous Et₂ O (400ml) at -78°. The resulting mixture was stirred at -78° for 1 hr, allowedto warm to room temperature, and stirred overnight. The Et₂ O wasremoved under vacuum to leave a white powder which was washed with waterand dried under vacuum to give 3.2 g (70%) of the title compound as awhite powder, m.p. 152°-153° C.

b.3(RS)-[[4-[(1-Naphthylsulfonyl)aminocarbonyl]phenyl]aminocarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³═4-[1-naphthyl-S(O₂)NHC(O)]φ, R⁴ ═H, A═NHCO, n=1)

1-Naphthalene sulfonamide, prepared according to Example 77a (0.64 g,3.09 mmol), was added to a stirred solution of material preparedaccording to Example 16 (1.5 g, 2.84 mmol), DMAP (0.38 g, 3.1 mmol),WSCDI (0.59 g, 3.08 mmol) and dry CH₂ Cl₂ (40 ml) under nitrogen at roomtemperature. The resulting reaction mixture was stirred at roomtemperature overnight before it was washed (1N HCl), dried (MgSO₄), andfiltered. The filtrate was concentrated under vacuum to a gummy residuewhich was purified by flash chromatography, (CH₂ Cl₂ then CH₂ Cl₂:MeOH:AcOH (98:1.9: 0.1) to give 0.76 g (36%) of the title compound as awhite powder; HPLC, t_(R) =10.08 & 16.38, Col A, CH₃ CN:H₂ O (30:70),FR=2.5.

Analysis calculated for: C₃₄ H₃₈ F₃ N₅ O₇ S.OH₂ O: C, 54.25; H, 5.49; N,9.30. Found: C, 54.56; H, 5.68; N, 8.85.

EXAMPLE 78 3(RS)-N² -(4-Hydroxycarbonylphenyl)aminocarbonyl-N⁶-phenylmethoxycarbonyl-L-lysyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₂)₄ NHC(O)OCH₂ φ, R³ ═4-[HOC(O)]φ,R⁴ ═H, A═NHCO, n=1) a. 2(RS),3(SR)-N²-(4-Ethoxycarbonylphenyl)aminocarbonyl-N⁶-phenylmethoxycarbonyl-L-lysyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₂)₄ NHC(O)OCH₂ O, R³═4-[EtOC(O)]φ, R⁴ ═H, A═NHCO, n=1)

Using the method of Example 15a, material prepared by the procedure ofExample 72a was allowed to react with ethyl 4-isocyanatobenzoate toprovide the title compound, isolated in 95% yield after purification byflash chromatography (gradient elution, CHCl₃ to MeOH:CHCl₃ (2:98), then(5:95)); TLC, R_(f) =0.41, MeOH:CHCl₃ (2.5:97.5).

b. 3(RS)-N² -(4-Ethoxycarbonylphenyl)aminocarbonyl-N⁶-phenylmethoxycarbonyl-L-lysyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₂)₄ NHC(O)OCH₂ φ, R³ ═4-[EtOC(O)]φ,R⁴ ═H, A═NHCO, n=1)

Using the method of Example 31c, the product of Example 78a was oxidizedto afford, after purification by flash chromatography (gradient elution,CHCl₃ to MeOH:CHCl₃ (2.5:97.5) to (5:95)), the title product (77%); TLC,R_(f) =0.48, MeOH:CHCl₃ (2.5:97.5).

c. 3(RS)-N² -(4-Hydroxycarbonylphenyl)aminocarbonyl-N⁶-phenylmethoxycarbonyl-L-lysyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₂)₄ NHC(O)OCH₂ φ, R³ ═4-[HOC(O)]φ,R⁴ ═H, A═NHCO, n=1)

Using the method of Example 14, material prepared according to theprocedure of Example 78b was converted into the title product andisolated in 85% yield; HPLC, t_(R) =4.71 & 6.76, Col A, CH₃ CN:H₂ O(40:60), FR=2.5.

Analysis calculated for: C₃₃ H₄₀ F₃ N₅ O₈.1.5H₂ O: C, 55.15; H, 6.03; N,9.74. Found: C, 54.90; H, 5.92; N, 9.29.

EXAMPLE 793(RS)-(4-Hydroxycarbonylphenyl)carbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[HOC(O)]φ, R⁴ ═H,A═CO n=1)

Using the method of Example 14, material prepared according to theprocedure of Example 84c was converted into the title product andisolated in 72% yield; HPLC, t_(R) =3.48 & 5.31, Col A, H₂ O:CH₃ CN(3:1), FR=2.0.

Analysis calculated for: C₂₄ H₃₀ F₃ N₃ O₆.1.0H₂ O: C, 54.23; H, 6.07; N,7.91. Found: C, 54.46; H, 6.05; N, 7.69.

EXAMPLE 803(RS)-Phenylsulphonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═φ, R⁴ ═H, A═S(O₂), n=1)a.2(RS),3(SR)-Phenylsulfonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═φ, R⁴ ═H, A═S(O₂),n=1)

NMM (0.24 g, 2.4 mmol) and benzenesulfonyl chloride (0.21 g, 1.2 mmol)were added to a solution of material prepared according to Example 61a(0.5 g, 1.1 mmol) in CH₂ Cl₂ (5 ml), and the reaction was stirredovernight at room temperature. The reaction was concentrated undervacuum; the residue was taken up in EtOAc and filtered; and the filtrateconcentrated under vacuum to give the crude product. The product waspartially purified by flash chromatography (gradient, MeOH:CHCl₃(2.5:97.5) to (5:95)) and finally purified by flash chromatography(gradient, Et₂ O:hexane (80: 20) to Et₂ O:hexane (90:10) to Et₂ O) togive the title product (0.118 g); TLC, R_(f) =0.33, Et₂ O.

b.3(RS)-Phenylsulfonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═φ, R⁴ ═H, A═S(O₂), n=1)

Using the method of Example 31c, the product of Example 80a was oxidizedto afford, after purification by flash chromatography (gradient,MeOH:CHCl₃ (0:100) to (2:98) to (5:95)), the title product (42%); HPLC,t_(R) =4.97 & 6.17, Col A, H₂ O:CH₃ CN (1:1), FR=1.0.

Analysis calculated for: C₂₁ H₂₈ F₃ N₃ O₅ S.H₂ O: C, 49.50; H, 5.93; N,8.25. Found: C, 49.70; H, 6.24; N, 7.67.

EXAMPLE 813(RS)-[1-(Ethoxycarbonyl)cyclopent-1-yl]carbonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═1-[CH₃ CH₂OC(O)]cyclopent-1-yl-, R⁴ ═H, A═CO, n=1) a.1-(Ethoxycarbonyl)cyclopentanecarboxylic acid

To a solution of diethyl 1,1-cyclopentane dicarboxylate (2.5 g, 11.68mol) in EtOH (10 ml) was added dropwise a solution of KOH (654 mg, 11.68mmol) in EtOH (10 ml) over 1/2 hour. The resulting mixture was stirredat room temperature for 96 hr, concentrated under vacuum, andpartitioned between H₂ O and EtOAc. The aqueous layer was acidified withconcentrated HCl and extracted with EtOAc. The EtOAc extracts werewashed (brine), dried (Na₂ SO₄), filtered, and concentrated under vacuumto give the product (1.73 g) as a clear oil.

b.2(RS),3(SR)-[1-Ethoxycarbonyl)cyclopent-1-yl)]carbonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═1-[CH₃ CH₂OC(O)]cyclopent-1-yl, R⁴ ═H, A═CO, n=1)

Using the method of Example 50a with the following ratios of reagents toone equivalent of the product prepared according to Example 81a: HOBT(3.3 equivalents), DCC (1.65 equivalents), TEA (1.5 equivalents) andmaterial prepared according to the procedure of Example 61a (1.0equivalent), and omitting the citric acid wash, the title product wasprepared, isolated by suction chromatography (gradient elution, Et₂O:hexane (1:1) to Et₂ O) in 46% yield; TLC, R_(f) =0.47, MeOH:CHCl₃(5:95).

Analysis calculated for: C₂₄ H₃₈ F₃ N₃ O₆ : C, 55.27; H, 7.34; N, 8.06.Found: C, 54.74; H, 5.93; N, 7.88.

c.3(RS)-[1-(Ethoxycarbonyl)cyclopent-1-yl)]carbonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃) CH₃, R² ═CH₃ CH₂, R³ ═1-[CH₃ CH₂OC(O)]-cyclopent-1-yl, R⁴ ═H, A═CO, n=1)

Using the method of Example 33c, the product of Example 81b was oxidizedto afford, after purification by flash chromatography (acetone:hexane(1:4)), the title product (37%); HPLC, t_(R) =6.68 & 8.31, Col A, H₂O:CH₃ CN (70:30), FR=2.0.

Analysis calculated for: C₂₄ H₃₆ F₃ N₃ O₆.1.1H₂ O: C, 53.44; H, 7.13; N,7.80. Found: C, 53.48; H, 6.97; N, 7.60.

EXAMPLE 82 3(RS)-(Tricyclo[3.3.1.1³. 7]dec-1-yl)sulfonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═1-adamantyl, R⁴ ═H,A═S(O₂), n=1) a. 1-Adamantane sulfinyl chloride

Aluminum trichloride (40 g, 3 mol) was added slowly to thionyl chloride(200 ml, 2.7 mol), and the mixture was cooled to -20°. Adamantane wasadded in portions over 21/2 hrs, and the resulting mixture was stirred 1hr and allowed to warm to room temperature. After the thionyl chloridewas removed under vacuum, the residue was diluted with CCl₄ ; and thealuminum trichloride was decomposed with ice and water. The layers wereseparated; and the organic layer was washed (brine), dried (Na₂ SO₄),filtered, and concentrated under vacuum. The residue was distilled undervacuum (1 torr, 133.3 Pascals) with a vigreaux column to give theproduct (28.8 g; bp 118°-128°) as a waxy solid; TLC, R_(f) =0.6-0.4,EtOAc:hexanes (15:85).

b. 2(RS),3(SR)-(Tricyclo[3.3.1.1³,7]dec-1-yl)sulfonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═1-adamantyl, R⁴ ═H,A═S(O), n=1

Using the method of Example 20a, material prepared according to theprocedure of Example 61a was allowed to react with material preparedaccording to Example 82a to provide the title compound, isolated in 61%yield after purification by suction flash chromatography (gradient, Et₂O:EtOAc (1:1) to EtOAc); TLC, R_(f) =0.53, MeOH:CHCl₃ (5:95).

Analysis calculated for: C₂₅ H₄₀ F₃ N₃ O₄ S.0.45H₂ O: C, 55.22; H, 7.58.Found: C, 55.05; H, 7.57.

c. 2(RS),3(SR)-(Tricyclo[3.3.1.1³,7]dec-1-yl)sulfonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═1-adamantyl, R⁴ ═H,A═S(O₂), n=1)

To a solution of the product of Example 82b (277 mg, 0.515 mmol) inacetone (25 ml) at reflux was added a satd acetone solution of KMnO₄ (60ml) dropwise over 1 hr. This was stirred 15 min at reflux, cooled,filtered through Celite®, and concentrated under vacuum. The crudeproduct was purified by flash chromatography (EtOAc:Et₂ O (4:6)) to givethe title product (180 mg) as a solid; TLC, R_(f) =0.67 & 0.70,MeOH:CHCl₃ (1:9).

Analysis calculated for: C₂₅ H₄₀ F₃ N₃ O₅ S: C, 54.43; N, 7.31; N, 7.62.Found: C, 54.49; N, 7.33; N, 7.39.

d. 3(RS)-(Tricyclo[3.3.1.1³,7]dec-1-yl)sulfonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³ ═1-adamantyl, R⁴ ═H,A═S(P₂), n=1)

Using the method of Example 33c, the product of Example 82c was oxidizedto afford, after purification by flash chromatography (acetone:hexanes(15: 85)), the title product (40%); HPLC, t_(R) =6.27 & 8.29, Col A, H₂O:CH₃ CN (1:1), FR=2.0.

Analysis calculated for: C₂₅ H₃₈ F₃ N₃ O₅ S.0.5H₂ O: C, 53.75; H, 7.04;N, 7.32. Found: C, 53.91; H, 7.11; N, 6.97.

EXAMPLE 833(RS)-[1-(Hydroxycarbonyl)cyclopent-1-yl]carbonyl-L-α-aminobutyryl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH₃ CH₂ --, R³═1-[HOC(O)]cyclopent-1-yl, R⁴ ═H, A═CO, n=1)

Using the method of Example 14, material prepared according to theprocedure of Example 81c was converted into the title product andisolated in 79% yield; HPLC, t_(R) =3.74 & 4.92, Col A, H₂ O:CH₃ CN(3:1), FR=2.0.

Analysis calculated for: C₂₂ H₃₂ F₃ N₃ O₆.0.35H₂ O: C, 53.08; H, 6.62;N, 8.44. Found: C, 53.04; H, 6.58; N, 8.16.

EXAMPLE 843(RS)-(4-Methoxycarbonylphenyl)carbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[CH₃ OC(O)]φ R⁴ ═H,A═CO, n=1) a. 4-Methoxycarbonylbenzenecarboxylic acid

Concentrated sulfuric acid (277.5 ml, 5.2 mol) was added dropwise over1/2 hr to a stirred solution of chromium (VI) oxide (299.25 g, 2.99 mol)and water (925 ml) at 0°. The resulting solution was added dropwise over1 hr to a stirred solution of methyl-4-(hydroxymethyl)benzoate (92.5 g,0.564 mol) and acetone (4.6 1) at 0°. The reaction mixture was allowedto warm to room temperature and stirred overnight. The supernatant wasdecanted before the black tar-like residue was extracted with acetone.The decanted supernatant and acetone extracts were combined andconcentrated under vacuum to leave a dark brown residue which wastriturated with cold water (4 liter). The precipitate which formed wascollected, washed three times with water (1 liter), and dried to give94.6 g (94%) of the title compound as white crystals, m.p. 218°-221° C.

b.2(RS),3(SR)-(4-Methoxycarbonylphenyl)carbonyl-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[CH₃ OC(O)]φ, R⁴═H A═CO, n=1)

WSCDI (10.27 g, 53.6 mmol) was added to a stirred solution of a compoundprepared according to Example 3d (17.54 g, 47.8 mmol), the product ofExample 84a (8.6 g, 47.8 mmol), HOBT (12.86 g, 95.3 mmol) and dry THF(400 ml) at 0° under nitrogen. The resulting reaction mixture wasstirred at 0° for 1 hr; then it was allowed to come to room temperatureand to stir overnight. The THF was removed under vacuum to leave an oilyresidue which was dissolved in EtOAc. The EtOAc solution was washed (1NHCl, satd aq, NaHCO₃, and brine), dried (MgSO₄), filtered, andconcentrated under vacuum to give 24.45 g of the crude product as a drywhite foam. Purification by flash chromatography (CHCl₃ :MeOH (97:3))produced the title compound (79%); HPLC, t_(R) =4.62 & 5.80, Col A, H₂O:CH₃ CN (55:45); FR=3.0.

c.3(RS)-(4-Methoxycarbonylphenyl)carbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[CH₃ OC(O)]φ, R⁴ ═H,A═CO, n=1)

Using the method of Example 31c, the product of Example 84b was oxidizedto afford, after purification by flash chromatography (CHCl₃ :MeOH(98:2)), the title product (69%); HPLC, t_(R) =4.51 & 6.82, Col A, H₂ O:CH₃ CN (55:45), FR=2.0.

Analysis calculated for: C₂₅ H₃₂ F₃ N₃ O₆.0.5H₂ O: C, 55.96; H, 6.19; N,7.83. Found: C, 55.90; H, 6.30; N, 7.93.

d.3(RS)-(4-Methoxycarbonylphenyl)carbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═4-(CH₃ OCO)φ, R⁴ ═H,A═CO, n=1)

A preferred method employing the oxidation described in D. B. Dess andJ. C. Martin, J. Org. Chem., 48, 4155-4156(1983) for the preparation ofthe title compound is as follows: To a stirred solution of Dess-Martinperiodinane (6.76 g, 15.96 mmol) and a product prepared using the methodof Example 84b (6.49 g, 12.25 mmol) in dry CH₂ Cl₂ (80 ml) undernitrogen was added TFA (1.82 g, 1.23 ml, 15.96 mmol). After the reactionmixture had been stirred overnight at room temperature, Et₂ O (about 3to 5 times the volume of CH₂ Cl₂) was added, and the mixture was pouredinto an aq solution of satd NaHCO₃ and Na₂ S₂ O₃ (17.63 g, 111.51 mmol).After 15 min of stirring, the organic layer was separated, washed (satdNaHCO₃, brine), dried (Na₂ SO₄), filtered, and concentrated to give thetitle product as a white foam (6.42 g, 99.4%); TLC, R_(f) =0.67 & 0.76;MeOH: CHCl₃ (3:97); HPLC, t_(R) =4.64 & 6.84, Col A, H₂ O:CH₃ CN(60:40), FR=2.0.

EXAMPLE 853(RS)-(4-Hydroxycarbonylphenyl)aminocarbonyl-L-phenylalanyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═φCH₂, R³ ═4-[HOC(O)]φ, R⁴ ═H, A═NHCO,n=1)

Using the method of Example 14, material prepared according to theprocedure of Example 76f was converted into the title product andisolated by flash chromatography (gradient, MeOH:CH₂ Cl₂ (4:96) to(10:90)) in 48% yield; HPLC, t_(R) =5.52 & 8.12, Col A, CH₃ CN:H₂ O(35:65), FR=2.0.

Analysis calculated for: C₂₈ H₃₁ F₃ N₄ O₆.H₂ O: C, 56.56; H, 5.59; N,9.42. Found: C, 56.58; H, 5.59; N, 9.22.

EXAMPLE 863(RS)-(4-Methoxycarbonylphenyl)methoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[CH₃ OC(O)]φCH₂ --,R⁴ ═H, A═OCO, n=1) a. (4-Methoxycarbonylphenyl)methyl 4-nitrophenylcarbonate

Using the method of Example 7a, but omitting the pH 7.0 wash, methyl4-hydroxymethylbenzoate was converted into the title compound which wasisolated by trituration with hexanes, washed with hexanes:EtOAc (1:1),and dried under vacuum to provide a 50% yield; TLC, R_(f) =0.75,EtOAc:hexane (1:1).

b.2(RS),3(SR)-(4-Methoxycarbonylphenyl)methoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH, R³ ═4-[CH₃ OC(O)]φCH₂, R⁴═H, A═OCO, n=1)

Using the method of Example 7b, material prepared by the procedure ofExample 3d was allowed to react with the product of Example 86a toprovide the title compound, which was isolated in 48% yield afterpurification by flash chromatography (acetone: hexanes (2:3)), TLC,R_(f) =0.63 & 0.68, MeOH:CHCl₃ (1:9).

Analysis calculated for: C₂₆ H₃₆ F₃ N₃ O₇ : C, 55.81; H, 6.48; N, 7.51.Found: C, 55.54; H, 6.39; N, 7.29.

c.3(RS)-(4-Methoxycarbonylphenyl)methoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[CH₃ OC(O)]φCH₂, R⁴═H, A═OCO, n=1)

Using the method of Example 33c, the product of Example 86b was oxidizedto afford, after purification by preparative TLC (EtOAc:Et₂ O (3:2)),the title product (10%); HPLC, t_(R) =4.32 & 6.44, H₂ O:CH₃ CH (1:1),FR=2.0.

Analysis calculated for: C₂₆ H₃₄ F₃ N₃ O₇.0.65H₂ O: C, 54.86; H, 6.25;N, 7.38. Found: C, 54.87; H, 6.25; N, 7.05.

EXAMPLE 87 3(RS)-[E-3-(4-Ethoxycarbonylphenyl)-1-oxoprop-2-enyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═E-4-[CH₃ CH₂O--C(O)]φCH═CH, R⁴ ═H, A═CO, n=1) a. Ethyl 4-formylbenzoate

A mixture of 4-formylbenzoic acid (25 g) conc sulfuric acid (2 ml) andEtOH (19.5 ml) was refluxed gently for 5 days in 100 ml of1,2-dichloroethane. The solvent was then stripped, and Et₂ O was addedto the residue. The Et₂ O solution was washed (satd aq NaHCO₃) dried(Na₂ SO₄), filtered, and evaporated. Bulb to bulb distillation afforded20.1 g (68%) of the title ester as a clear liquid, bp 145°-150° (2,900Pascals, 22 torr).

b. E-(4-Ethoxycarbonyl)benzenepropenoic acid

A mixture of the product of Example 87a (8.9 g), malonic acid (10.4 g),and piperidine (1 ml) in 25 ml of pyridine was heated on a steam bathfor 3 hr. After the solvent was evaporated and the residue slurried in200 ml of water, the pH was adjusted to 6 with acetic acid. Theprecipitate was collected and air dried. Crystallization of the materialfrom EtOH gave 10.1 g (92%) of the title acid as sparkling whitecrystals, mp 220.5°-221°.

c.2(RS),3(SR)-[E-3-(4-Ethoxycarbonylphenyl)-1-oxoprop-2-enyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═E-[4-CH₃ CH₂O--C(O)]φCH═CH, R⁴ ═H, A═CO, n=1)

Using the method of Example 32a, material prepared by the procedure ofExample 3d was allowed to react with the product of Example 87b toprovide the title compound, isolated in 88% yield; TLC, R_(f) =0.14 &0.18, MeOH:CH₂ Cl₂ (5:95).

d.3(RS)-[E-3-(4-Ethoxycarbonylphenyl)-1-oxoprop-2-enyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═E-[4-CH₃ CH₂OC(O)]φ--HC═CH, R⁴ ═H, A═CO, n=1)

Using the method of Example 61c, the product of Example 87c was oxidizedto afford, after purification by flash chromatography (MeOH: CH₂ Cl₂(2:98)), the title product (65%); TLC, R_(f) =0.23, MeOH:CH₂ Cl₂ (5:95).

Analysis calculated for: C₂₈ H₃₆ F₃ N₃ O₆ : C, 59.25; H, 6.39; N, 7.40.Found: C, 59.14; H, 6.75; N, 7.21.

EXAMPLE 883(RS)-(2-Ethoxycarbonylphenyl)aminocarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═2-[CHBCH₂ OC(O)]φ, R⁴═H, A═NHCO, n=1) a.2(RS),3(SR)-(2-Ethoxycarbonylphenyl)aminocarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═2-[CH₃ CH₂ OC(O)]φ,R⁴ ═H, A═NHCO, n=1)

Using the method of Example 15a, material prepared by the procedure ofExample 3d was allowed to react with ethyl 2-isocyanatobenzoate toprovide the title compound, which was isolated in 66% yield afterpurification by flash chromatography (EtOAc: hexane (60:40)); TLC, R_(f)=0.48 & 0.57, MeOH:CHCl₃ (5:95).

b.3(RS)-(2-Ethoxycarbonylphenyl)aminocarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxo-pentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═2-(CH₃ CH₂ OCO)φ, R⁴═H, A═NHCO, n=1)

A modification of the procedure of Example 54b was done using theindicated ratios of the product of Example 88a (1 equivalent), oxalylchloride (2 equivalents), DMSO (4 equivalents) with the reaction mixturecooled to -45° for these above-listed additions and warmed to -20° foraddition of the TEA (instead of diisopropylethylamine). The work upincluded washing (1N HCl, satd aq NaHCO₃, 10% aq NaOCl, brine). Thetitle product was obtained after purification by flash chromatography(Et₂ O:hexane (4:1)) in 74% yield; HPLC, t_(R) =6.95 & 10.46, Col A, CH₃CN :H₂ O (35:65), FR=2.0.

Analysis calculated for: C₂₆ H₃₅ F₃ N₄ O₆.0.75 H₂ O: C, 54.78; H, 6.45;N, 9.83. Found: C, 54.73; H, 6.34; N, 9.51.

EXAMPLE 893(RS)-4-[(4-Nitrophenyl)sulfonylaminocarbonyl]phenylcarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[(4-NO₂φ)S(O₂)NHCO]φ, R⁴ ═H, A═CO, n=1)

4-Nitrobenzene sulfonamide (0.196 g, 0.97 mmol) was added to a stirredsolution of the product of Example 79 (0.5 g, 0.97 mmol), DMAP (0.12 g,0.97 mmol), DCC (0.22 g, 0.97 mmol), and dry CH₂ Cl₂ (30 ml) undernitrogen at room temperature. The resulting mixture was stirredovernight at room temperature and filtered. The filtrate was washed (1NHCl), dried (MgSO₄), filtered, and concentrated under vacuum to a yellowresidue which was purified by flash chromatography, (CHCl₃ :MeOH:AcOH(90:9.8:0.2)) to give 0.29 g (43%) of the title compound as a whitepowder; HPLC, t_(R) =4.26 & 8.42, Col A, H₂ O:CH₃ CN (4:1), FR=2.0.

Analysis calculated for: C₃₀ H₃₄ F₃ N₅ O₉.H₂ O: C, 50.34; H, 5.06; N,9.78. Found: C, 50.03; H, 4.92; N, 9.43.

EXAMPLE 903(RS)-Phenylmethoxycarbonyl-L-glutamyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamidephenylmethyl ester (Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═--(CH₂)₂ C(O)OCH₂ φ,R³ ═φCH₂ --, R⁴ ═H, A═OCO, n=1) a.2(RS),3(SR)-Phenylmethoxycarbonyl-L-glutamyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₂)₂ C(O)OCH₂ φ, R³ ═φCH₂ --, R⁴═H, A═OCO, n=1).

Using the method of Example 84b, CBZ-glutamic acid gamma-benzylester wasallowed to react with material prepared according to the method ofExample b to provide the title compound, isolated in 64% yield afterpurification by flash chromatography (gradient elution, hexane:Et₂ O(1:3) to Et₂ O); TLC, R_(f) =0.61, Et₂ O.

b.3(RS)-Phenylmethoxycarbonyl-L-glutamyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamidephenylmethyl ester (Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₂)₂ C(O)OCH₂ φ,R³ ═φCH₂ --, R⁴ ═H, A═OCO, n=1)

Using the method of Example 54b, the product of Example 90a was oxidizedto afford, after purification by flash chromatography (gradient,hexane:Et₂ O (2:8) to (1:9)), the title product (30%); HPLC, t_(R) =6.12& 8.48, Col A, CH₃ CN:H₂ O (1:1), FR=3.0.

Analysis calculated for: C₃₁ H₃₆ F₃ N₃ O₇.2H₂ O: C, 56.78; H, 6.15; N,6.41. Found: C, 56.98; H, 5.74; N, 6.12.

EXAMPLE 91 3S(or R)-(Tricyclo[3.3.1.1³,7]dec-1-yl)sulfonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═1-adamantyl, R⁴ ═H,A═S(O₂), n=1) a. 2(RS),3(SR)-(Tricyclo [3.3.1.1³,7]dec-1-yl)═sulfinyl-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH, R³ ═1-adamantyl, R⁴ ═H,A═S(O), n=1)

Using the method of Example 20a, material prepared by the procedure ofExample 3d was allowed to react with product from Example 82a to providethe title compound which was isolated by flash chromatography (EtOAc:Et₂O (2:3)); TLC, R_(f) =0.75, MeOH:CHCl₃ (1:9).

b. 2(RS),3(SR)-(Tricyclo[3.3.1.1³,7]dec-1-yl)sulfonyl-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃) CH₃, R² ═(CH₃)₂ CH--, R³ ═1-adamantyl, R⁴ ═H,A═S(O₂), n=1)

Using the method of Example 82c, the product of Example 91a wasconverted into the title product, isolated in 60% yield afterpurification by flash chromatography (EtOAc:hexane (2:3)); TLC, R_(f)=0.29 & 0.35, EtOAc:hexane (1:1).

Analysis calculated for: C₂₆ H₄₂ F₃ N₃ O₅ S.2.5H₂ O: C, 51.13; H, 7.75;N, 6.88. Found: C, 51.12; H, 7.03; N, 6.40.

c. 3S(or R)-Tricyclo[3,3.1³,7]dec-1-yl)sulfonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═1-adamantyl, R⁴ ═H,A═S(O₂), n=1).

Using the method of Example 33c, the product of Example 91b was oxidizedto afford, after purification by flash chromatography (EtOAc:hexane(1:1)), the title product (57%) as one substantially pure isomer; HPLC,t_(R) =3.01, Col A, H₂ O:CH₃ CN (45:55), FR=2.0.

Analysis calculated for: C₂₆ H₄₀ F₃ N₃ O₅ S.O.4H₂ O: C, 54.70; H, 7.20.Found: C, 54.89; H, 7.17.

EXAMPLE 923(RS)-(4-Ethoxycarbonylphenyl)aminocarbonyl-L-phenylglycyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═φ, R³ ═4-[CH₃ CH₂ O--C(O)]φ, R⁴ ═H,A═NHCO, n=1) a.2(RS),3(SR)-Phenylmethoxycarbonyl-L-phenylglycyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═φ, R³ ═OCH₂ --, R⁴ ═H, A═OCO, n=1)

Using the method of Example 50a, material prepared according to theprocedure of Example 76b was allowed to react with CBZ-L-phenyl-glycineto provide, after purification by flash chromatography (MeOH:CH₂ Cl₂(5:95)), the title product (95%); TLC, R_(f) =0.13 & 0.19, MeOH:CH₂ Cl₂(5:95).

b.2(RS),3(SR)-L-Phenylglycyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula IVb, R¹ ═CH(CH₃)CH₃, R² ═φ, R⁴ ═H, n=1).

Using the method of Example 2b, material prepared according to theprocedure of Example 92a was converted into the title product in 100%yield.

c.2(RS),3(SR)-(4-Ethoxycarbonylphenyl)aminocarbonyl-L-phenylglycyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═φ, R³ ═4-[CH₃ CH₂ OC(O)]φ, R⁴ ═H,A═NHCO, n=1)

Using the method of Example 15a, material prepared according to theprocedure of Example 92b was allowed to react with ethyl4-isocyanatobenzoate to provide the title product (869°); TLC, R_(f)=0.24 & 0.27, MeOH:Et₂ O (1:99).

d.3(RS)-(4-Ethoxycarbonylphenyl)aminocarbonyl-L-phenylglycyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)--CH₃, R² ═φ, R³ ═4-[CH₃ CH₂ OC(O)]φ, R⁴ ═H,A═NHCO, n=1)

Using the method of Example 31c, the product of Example 92c was oxidizedto afford, after purification by flash chromatography (gradient, Et₂ Oto CH₃ CN: Et₂ O (1:99)), the title product (82%); HPLC, t_(R) =8.88 &10.82, Col A, CH₃ CN:H₂ O (45:55); FR=2.0.

Analysis calculated for: C₂₉ H₃₃ F₃ N₄ O₆.0.64H₂ O: C, 56.77; H, 5.80;N, 8.75. Found: C, 56.62; H, 5.78; N, 8.78.

EXAMPLE 93 3(RS)-Phenylmethoxycarbonyl-L-[5-(phenylsulfonylamino)glutamyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═φS(O₂)NHC(O)(CH₂)₂, R³ ═φCH₂, R⁴ ═H,A═OCO, n=1) a.3(RS)-Phenylmethoxycarbonyl-L-glutamyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═HOCO(CH₂)₂, R³ ═φCH₂, R⁴ ═H, A═OCO,n=1)

Using the method of Example 14, material prepared according to theprocedure of Example 90b was converted into the title product; TLC,R_(f) =0.27, MeOH: CHCl₃ :AcOH (2.5:95:0.1).

b.3(RS)-Phenylmethoxycarbonyl-L-[5-(phenylsulfonylamino)glutamyl]-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)--CH₃, R² ═φS(O₂)NHC(O)(CH₂)₂, R³ ═φCH₂ --, R⁴═H, A═OCO, n=1)

Using the method of Example 77b, material prepared according to theprocedure of Example 93a was allowed to react with benzenesulfonamide toprovide, after purification by flash chromatography (gradient, MeOH:Et₂O (2.5:97.5) to (5:95)), the title product (40%); HPLC, t_(R) =7.38 &10.35, Col A, H₂ O:CH₃ CN (65:35), FR=2.5.

Analysis calculated for: C₃₀ H₃₅ F₃ N₄ O₈ S.1.5H₂ O: C, 51.79; H, 5.51;N, 8.19. Found: C, 51.70; H, 5.24; N, 7.89.

EXAMPLE 943(RS)-[4-(Phenylsulfonylaminocarbonyl)phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib R¹ ═CH(CH)CH R² ═(CH₃)₂ CH--, R³ ═4-[φS(O₂)NH--C(O)]φ, R⁴═H, A═CO, n=1)

Using the method of Example 89, material prepared according to theprocedure of Example 79 was allowed to react with benzenesulfonamide toprovide, after purification by flash chromatography (EtOAc: Et₂ O:AcOH(25:74.9:0.1)), the title product (33%); HPLC, t_(R) =3.71 & 5.65, ColA, H₂ O: CH₃ CN (3: 1); FR=2.0.

Analysis calculated for: C₃₀ H₃₅ F₃ N₄ O₇ S.1.25H₂ O: C, 53.36; H, 5.59;N, 8.29. Found: C, 53.75; H, 5.64; N, 7.72.

EXAMPLE 953(RS)-[4-[(4-Bromophenyl)sulfonylaminocarbonyl]phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³═4-[(4-Brφ)S(O₂)NHC(O)]φ, R⁴ ═H, A═CO, n=1) a. 4-Bromobenzenesulfonamide

Using the procedure of Example 77a, 4-bromobenzenesulfonyl chloride(10.0 g, 39.6 mmol) was converted into the title product, obtained aswhite crystals (8.45 g, 92%); m.p. 163°-165°.

b.3(RS)-[4-[(4-Bromophenyl)sulfonylaminocarbonyl]phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[(4-Br-φ)S(O₂)NHC(O)]φ, R⁴ ═H, A═CO, n=1)

Using the method of Example 89, material prepared according to theprocedure of Example 79 was allowed to react with the product of 95a toprovide, after purification by recrystallization from hexane/Et₂ O, thetitle product (509°); HPLC, t_(R) =5.25 & 7.84, Col A, H₂ O:CH₃ CN(77.5:22.5), FR=2.0.

Analysis calculated for: C₃₀ H₃₄ BrF₃ N₄ O₇ S.0.75H₂ O: C, 48.36; H,4.80; N, 7.52. Found: C, 48.61; H, 4.89; N, 7.18.

EXAMPLE 963(RS)-4-(1-Naphthylsulfonylamino)-1,4-dioxobutyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² (CH₃)₂ CH--, R³═1-naphthyl-S(O₂)NHC(O)(CH₂)₂, R⁴ ═H, A═CO, n=1)

Using the method of Example 89 material prepared according to theprocedure of Example 14 was allowed to react with1-naphthalenesulfonamide to provide, after purification by flashchromatography (MeOH:CHCl₃ (5:95)), the title product (46%); HPLC, t_(R)=4.09 & 6.57, Col A, H₂ O:CH₃ CN (60:40), FR=2.0.

Analysis calculated for: C₃₀ H₃₇ F₃ N₄ O₇ S.0.5H₂ O: C, 54.29; H, 5.77;N, 8.44. Found: C, 54.33; H, 6.01; N, 8.09.

EXAMPLE 973(RS)-[2-(4-Aminocarbonylphenoxy)-1-oxoethyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[[H₂ NC(O)]φOCH₂, R⁴═H, A═CO, n=1) a. 4-Aminocarbonylphenoxyacetic acid methylester

A mixture of p-hydroxybenzamide (3.43 g), methyl bromoacetate (2.37 ml)and K₂ CO₃ (3.45 g) was stirred for 12 hr in 25 ml of DMF. The reactionmixture was diluted with water (150 ml); the solid was filtered, washedwith water, and air dried. Crystallization from ethanol gave 3.3 g (63%)of the title compound as white crystals.

b. 4-Aminocarbonylphenoxyacetic acid

A mixture of the product of Example 97a (3.3 g) in 0.5 N NaOH (30 ml)was stirred for 3 hr. The solution was filtered and the filtrate madeacidic (pH 1) with 1N HCl. The solid was filtered and air dried to yield3.0 g (97%) of the title acid as a white powder; mp 255°-256°.

c.2(RS),3(SR)-[2-(4-aminocarbonylphenoxy)-1-oxoethyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[H₂ NC(O)]φOCH₂,R⁴ ═H, A═CO, n=1)

Using the method of Example 32a, material prepared by the procedure ofExample 5d was allowed to react with material prepared according toExample 97b to provide the title compound, isolated in 33% yield; TLC,R_(f) =0.27 & 0.31, MeOH:CH₂ Cl₂ (1:9).

d.3(RS)-[2-(4-Aminocarbonylphenoxy)-1-oxoethyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[H₂ NC(O)]φOCH₂, R⁴═H, A═CO, n=1)

Using the method of Example 61c, the product of Example 97c was oxidizedto afford, after purification by flash chromatography (MeOH:CH₂ Cl₂(4:96)), the title product (35%); TLC, R_(f) =0.37, MeOH:CHCl₃ (1:9).

Analysis calculated for: C₂₅ H₃₃ F₃ N₄ O₆.1.5H₂ O: C, 52.72; H, 6.37; N,9.83. Found: C, 52.78; H, 6.03; N, 9.65.

EXAMPLE 983(RS)-(4-Hydroxycarbonylphenyl)methoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[HOC(O)]φCH₂, R⁴ ═H,A═OCO, n=1)

Using the method of Example 14, material prepared according to theprocedure of Example 86c was converted into the title product andisolated by preparative TLC (MeOH:CHCl₃ (15:85)) in 45% yield; HPLC,t_(R) =2.27 & 3.02, Col A, H₂ O:CH₃ CN (60:40), FR=2.0.

Analysis calculated for: C₂₅ H₃₂ F₃ N₃ O₇.2 H₂ O: C, 51.81; H, 6.26; N,7.25. Found: C, 51.75; H, 5.63; N, 7.15.

EXAMPLE 993(RS)-[4-[4-(2-Amino-2-oxoethyl)phenoxy]-1-oxobutyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH, R³ ═4-[H₂ NC(O)CH₂]φO(CH₂)₃, R⁴ ═H, A═CO, n=1) a. 4-(4-Aminocarbonylphenoxy)butanoic acidethyl ester

A mixture of p-hydroxyphenylacetamide (3.8 g), ethyl 4-bromobutyrate(3.6 ml) and K₂ CO₃ (3.45 g) was stirred for 12 hr in DMF (30 ml). Themixture was diluted with water (100 ml); the solid was filtered and airdried. Crystallization of the solid from ethanol gave 4 g (60%) of thetitle compound as white crystals; mp 144.5°-145.5°.

b. 4-(4-Aminocarbonylphenoxy)butanoic acid

A mixture of the product of Example 99a (3.97 g) in 1N NaOH (20 ml) wasstirred overnight at room temperature. The solution was filtered andmade acidic with 1N HCl. The solid was filtered and dried under highvacuum to yield 3 g (82%) of the title compound as a white powder; m.p.162.5°-164°.

c.2(RS),3(SR)-[4-[4-(2-Amino-2-oxoethyl)phenoxy]-1-oxobutyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[H₂ NC(O) CH₂]φO(CH₂)₃, R⁴ ═H, A═CO, N=1)

Using the method of Example 32a, material prepared by the procedure ofExample 5d was allowed to react with the product of Example 99b toprovide the title compound, isolated in 71% yield; TLC, R_(f) =0.28 &0.31, MeOH:CHCl₃ (1:9).

d.3(RS)-[4-(2-amino-2-oxoethyl)phenoxy]-1-oxobutyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[H₂ NC(O)CH₂]φO(CH₂)₃, R⁴ ═H, A═CO, n=1)

Using the method of Example 61c, the product of Example 99c was oxidizedto afford, after purification by flash chromatography (MeOH:CH₂ Cl₂(4:96)), the title product (32%); HPLC, t_(R) =2.11 & 3.01, Col B, H₂ O:CH₃ CN: THF :TFA (55: 35: 15:0.1), FR=2.0.

Analysis calculated for: C₂₈ H₃₉ F₃ N₄ O₆.5H₂ O: C, 56.65; H, 6.79; N,9.43. Found: C, 56.83; H, 6.98; N, 9.24.

EXAMPLE 100 3(RS)-E-[3-(4-Hydroxycarbonylphenyl)-1-oxoprop-2-enyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═E-4-[HOC(O)]φCH═CH--,R⁴ ═H, A═CO, n=1)

Using the method of Example 14, material prepared according to theprocedure of Example 87d was converted into the title product in 88%yield; HPLC, t_(R) =2.6 & 3.4, Col B, H₂ O:CH₃ CN: THF:TFA (55:35:15:0.1), FR=1.5.

Analysis calculated for: C₂₆ H₃₂ F₃ N₃ O₆ 0.35H₂ O: C, 57.21; H, 6.03;N, 7.96. Found: C, 57.40; H, 6.40; N, 7.38.

EXAMPLE 1013(RS)-[2-(4-Ethoxycarbonylphenoxy)-1-oxoethyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[CH₃ CH₂OC(O)]φOCH₂, R⁴ ═H, A═CO, n=1) a. Ethyl4-[2-Oxo-2-(phenylmethoxy)ethoxy]benzoate

A mixture of ethyl p-hydroxybenzoate (4.98 g), benzyl bromoacetate (4.75ml) and K₂ CO₃ (4.14 g) was stirred for 15 hr in 30 ml of DMF. Thereaction mixture was diluted with water (200 ml) and extracted with a1:1 ether:hexane mixture. The combined organic extracts were washed(water, brine), dried (Na₂ SO₄), filtered, and evaporated leaving 9.3 g,(99%) of the title compound as a heavy oil; TLC, R_(f) =0.71, Et₂ O:hexane (1:1).

b. Ethyl 4-(2-Hydroxy-2-oxoethoxy)benzoate

A solution of the product of Example 101a (2.0 g) in EtOH (50 ml) washydrogenated at 170,000 Pascals (10 psi) using 10% Pd/C (200 mg). After20 min the reaction was complete and the reaction mixture was filteredthrough a pad of Celite® and concentrated under vacuum. The residue wascrystallized from methyl tert-butyl ether/hexane affording 900 mg (63%)of the title compound as fine white needles; mp 129°-130°.

c.2(RS),3(SR)-[2-(4-Ethoxycarbonylphenoxy)-1-oxoethyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[CH₃ CH₂OC(O)]φOCH₂, R⁴ ═H, A═CO, n=1)

Using the method of Example 32a, material prepared by the procedure ofExample 5d was allowed to react with the product of Example 101b toprovide the title compound, isolated in 92% yield; TLC, R_(f) =0.47 &0.53, MeOH:CH₂ Cl₂ (1:9).

d.3(RS)-[2-(4-Ethoxycarbonylphenoxy)-1-oxoethyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH, R³ ═4-[CH₃ CH₂ OC(O)]φOCH₂,R⁴ ═H, A═CO, n=1)

Using the method of Example 61c, the product of Example 101c wasoxidized to afford, after purification by flash chromatography (MeOH:CH₂ Cl₂ (2: 98)), the title product (41%); TLC, R_(f) =0.37, MeOH:CHCl₃(1:9).

Analysis calculated for: C₂₇ H₃₆ F₃ N₃ O₇ : C, 56.74; H, 6.35; N, 7.35.Found: C, 56.40; H, 6.50; N, 7.12.

EXAMPLE 1023(RS)-[3-(4-Ethoxycarbonylphenyl)-1-oxopropyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH, R³ ═4-[CH₃ CH₂ OC(O)]φ(CH₂)₂--, R⁴ ═H, A═CO, n=1) a. 4-Ethoxycarbonylbenzenepropanoic acid

A solution of 4-carbethoxycinnamic acid (4.9 g) in EtOH (120 ml) washydrogenated over 5% Rh/C (485 mg) at atmospheric pressure for 21 hr.The solution filtered and stripped. The residue was crystallized fromcyclohexane to afford 2.23 g (46%) of the title compound as whitecrystals; mp 108.5°-110.5°.

b.2(RS),3(SR)-[3-(4-Ethoxycarbonylphenyl)-1-oxopropyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[CH₃ CH₂OC(O)]φ(CH₂)₂ --, R⁴ ═H, A═CO, n=1)

Using the method of Example 32a, material prepared by the procedure ofExample 5d was allowed to react with the product of Example 102a toproduce the title compound, isolated in 83% yield after purification byflash chromatography (MeOH:CH₂ Cl₂ (4:96)); TLC, R_(f) =0.33 & 0.38,MeOH:CH₂ Cl₂ (5:95).

c.3(RS)-[3-(4-Ethoxycarbonylphenyl)-1-oxopropyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[CH₃ CH₂OC(O)]φ(CH₂)₂ --, R⁴ ═H, A═CO, n=1)

Using the method of Example 84d, the product of Example 102b wasoxidized to afford the title product (97%).

Analysis calculated for: C₂₈ H₃₈ F₃ N₃ O₆.0.65 H₂ O: C, 57.85; H, 6.81;N, 7.23. Found: C, 57.89; H, 6.83; N, 6.98.

EXAMPLE 1033(RS)-4-Hydroxybenzoyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-(HO)φ, R⁴ ═H, A═CO,n=1) a.2(RS),3(SR)-4-Hydroxybenzoyl-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-(HO)φ, R⁴ ═H,A═CO, n=1)

Using the method of Example 84b, material prepared by the procedure ofExample 5d was allowed to react with 4-hydroxybenzoic acid to providethe title compound which was isolated in 65% yield after purification byflash chromatography (EtOAc:Et₂ O (15:85)); TLC, R_(f) =0.43, EtOAc:Et₂O (15:85).

Analysis calculated for: C₂₃ H₃₂ F₃ N₃ O₅.0.6H₂ O: C, 55.43; H, 6.71; N,8.43. Found: C, 55.76; H, 6.62; N, 8.03.

b.3(RS)-4-Hydroxybenzoyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-(HO)φ, R⁴ ═H, A═CO,n=1)

The product of Example 103a was oxidized by the method of Example 33cwith the following, modified workup: The crude residue was dissolved inMeOH and stirred with aq K₂ CO₃ (5 ml) at room temperature for 16 hr.After the mixture was partially concentrated under vacuum, it wasacidified with conc HCl and extracted with EtOAc. The EtOAc solution waswashed (brine), dried (Na₂ SO₄), filtered, and concentrated to a residuewhich was purified by flash chromatography (EtOAc:Et₂ O (1:9)) to affordthe title compound in 38% yield; HPCL, t_(R) =3.54 & 4.92, Col A, CH₃CN:H₂ ^(O) (35:65), FR=2.0.

Analysis calculated for: C₂₃ H₃₀ F₃ N₃ O₅.1.2 H₂ O: C, 54.47; H, 6.44;N, 6.29. Found: C, 54.83; H, 6.49; N, 7.89.

EXAMPLE 1043(RS)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2oxopentyl)]-L-prolinamide (Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH, R³═4-[(4-Clφ)S(O₂)NHC(O)]φ--, R⁴ ═H, A═CO, n=1)

Using the method of Example 77b, material prepared according to theprocedure of Example 79 was allowed to react with4-chlorobenzenesulfonamide to provide, after purification by flashchromatography (MeOH:CH₂ Cl₂ (3:97)) and acidification of thechromatographed product with MeOH and 1N HCl as described in Example121d, the title product (66%), HPLC, t_(R) =4.26 & 6.07, Col A, H₂ O:CH₃CN:THF:TFA (55:35:15:0.1).

EXAMPLE 1053(RS)-[3-(4-Hydroxycarbonylphenyl)-1-oxopropyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[HOC(O)]φ(CH₂)₂, R⁴═H, A═CO, n=1)

Using the method of Example 14, material prepared according to theprocedure of Example 102c was converted into the title product in 81%yield; HPLC, t_(R) =2.6 & 3.4, Col B, H₂ O:CH₃ CN:THF:TFA (55:35:15:0.1).

Analysis calculated for: C₂₆ H₃₄ F₃ N₃ O₆ : C, 57.66; H, 6.33; N, 7.76.Found: C, 56.98; H, 6.49; N, 7.35.

EXAMPLE 1063(RS)-[3-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]phenyl]-1-oxopropyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³═4-[(4-Clφ)S(O₂)NHC(O)]φ(CH₂)₂, R⁴ ═H, A═CO, n=1)

Using the method of Example 77b, material prepared according to theprocedure of Example 105 was allowed to react with4-chlorobenzenesulfonamide to provide, after purification by flashchromatography (MeOH:CH₂ Cl₂ (5:95)), the title product (90%); HPLC,t_(R) =3.96 & 5.73, Col B, H₂ O:CH₃ CN:THF:TFA (55:35:15: 0.1), FR=3.0.

Analysis calculated for: C₃₂ H₃₈ C₁ F₃ N₄ O₇ S.1.7 H₂ O: C, 51.53; H,5.59; N, 7.51. Found: C, 51.72; H, 5.40; N, 7.24.

EXAMPLE 1073(RS)-E-[3-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]phenyl]-1-oxoprop-2-enyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³═E-[4-[(4-Clφ)S(O₂)NHC(O)]φ--CH═CH--, R⁴ ═H, A═CO, n=1)

Using the method of Example 77b, material prepared according to theprocedure of Example 100 was allowed to react with4-chlorobenzenesulfonamide to provide, after purification by flashchromatography (MeOH:CH₂ Cl₂ (5:95)), the title product (97%); HPLC,t_(R) =4.73 & 6.68, Col B, H₂ O:CH₃ CN:THF:TFA (55:35:15: 0.1), FR=3.0.

Analysis calculated for: C₃₂ H₃₆ C₁ F₃ N₄ O₇ S.1.7 H₂ O: C, 51.67; H,5.33; N, 7.53. Found: C, 51.72; H, 5.40; N, 7.24.

EXAMPLE 1083(RS)-[1-[4-[[(4-Bromophenyl)sulfonyl][phenylmethyl]aminocarbonyl]phenyl]-1-oxomethyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[(4-Brφ)S(O₂)N(CH₂φ)C(O)]φ--, R⁴ ═H, A═CO, n=1) a.4-Bromo-N-(phenylmethyl)benzenesulfonamide

4-Bromobenzenesulfonyl chloride (14.05 g, 55 mmol) was added to astirred solution of benzylamine (5.36 g, 50 mmol) and pyridine (400 ml)under nitrogen at room temperature. The resulting reaction mixture wasstirred for 1 hr; then it was poured onto ice/water (800 ml) to form ayellow precipitate which was filtered and recrystallized from EtOH/waterto give 9.44 g (53%) of the title compound as off-white needles, mp116°-117° C.

Analysis calculated for: C₁₃ H₁₂ BrNO₂ S: C, 47.87; H, 3.71; N, 4.29.Found: C, 48.02; H, 3.78; N, 4.25.

b. 1,1-Dimethylethyl4-[[(4-bromophenyl)sulfonyl]-[phenylmethyl]aminocarbonyl]benzoate

DMAP (1.81 g, 14.84 mmol) was added to a stirred solution of the productof Example 108a (4.4 g, 13.49 mml) and CH₂ Cl₂ (150 ml) at roomtemperature. To the resulting solution, WSCDI (2.84 g, 14.84 mmol) andterephthalic acid mono t-butylester (3.0 g, 13.49 mmol) weresuccessively added. The reaction mixture was stirred at room temperatureovernight and concentrated under vacuum to leave a residue which wasdissolved in EtOAc. The EtOAc solution was washed (20% aq citric acidsolution, brine, water), dried (MgSO₄), filtered, and concentrated undervacuum to leave an oily residue. This residue was dissolved in warm EtOHand allowed to cool. The white crystals which formed were filtered,washed with cold EtOH, and dried under high vacuum to give 5.72 g (80%)of the title compound as white crystals; m.p. 120°-122° C.

Analysis calculated for: C₂₅ H₂₄ BrNO₅ S: C, 56.61; H, 4.56; N, 2.64.Found: C, 56.84; H, 4.68; N, 2.60.

c. 4-[[(4-Bromophenyl)sulfonyl][phenylmethyl]aminocarbonyl]benzoic acid

The product of Example 108b (5.30 g, 10 mmol) was added to TFA (50 ml)at 0° and dissolved immediately upon addition. After about 10 min awhite precipitate formed; stirring was continued for 1/2 hr before themixture was filtered. The collected solid was washed with water andrecrystallized from hot absolute EtOH to give 4.0 g (84%) of the titlecompound as a white powder; m.p. 193°-194° C.

d.2(RS),3(RS)[1-[4-[[(4-Bromophenyl)sulfonyl][phenylmethyl]aminocarbonyl]phenyl]-1-oxomethyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³═4-[[(4-Brφ)S(O)₂)][φCH₂ ]NCO]φ, R⁴ ═H, A═CO, n=1

WSCDI (0.44 g, 2.3 mmol) was added to a stirred solution of the productof Example 108c (1.0 g, 2.1 mmol), material prepared according toExample 5d (0.85 g, 2.3 mmol), HOBT (0.28 g, 2.1 mmol) and dry THF undernitrogen at 0°. The resulting reaction mixture was stirred at 0° C. for15 min; then it was allowed to warm to room temperature and stirred for4 hr. The THF was removed under vacuum to leave a brownish residue whichwas dissolved in EtOAc. The EtOAc solution was washed (1N HCl, satdNaHCO₃, brine) and dried (MgSO₄), filtered, and concentrated undervacuum to leave a residue (1.6 g). A (1.27 g) portion of this residuewas recrystallized from methyl t-butyl ether/hexane to give 0.64 g (49%overall yield) of the title compound as a white powder; TLC, R_(f) =0.59& 0.64, CHCl₃ :CH₃ OH (95:5); HPLC; t_(R) =14.34 & 15.26, Col B, H₂O:CH₃ CN:THF:TFA (55:35:15:0.1), FR=3.0.

e.3(RS)-[1-[4-[[(4-Bromophenyl)sulfonyl][phenylmethyl]aminocarbonyl]phenyl]-1-oxomethyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[[(4-Brφ)S(O₂)]N(CH₂ φ)C(O)]φ, R⁴ ═H, A═CO, n=1)

A solution of the product of Example 108d (300 mg, 0.364 mmol) in CH₂Cl₂ (2 ml) was added to a stirred mixture of a Dess-Martin periodinane(1.54 g, 3.63 mmol) and dry CH₂ Cl₂ (10 ml) under nitrogen at roomtemperature. To the resulting mixture, TFA (0.41 g, 3.63 mmol) wasadded; whereupon the mixture immediately became clear; then, after 10min, became cloudy. Stirring was continued overnight before EtOAc (50ml) was added, and the resulting mixture was poured into saturated aqNaHCO₃ (100 ml) containing 4 g of Na₂ S₂ O₃. The two phase mixture wasstirred vigorously for 10 min. The organic layer was separated, washed(satd NaHCO₃ (100 ml), brine (100 ml)), dried (MgSO₄), filtered,concentrated under vacuum, and dried under high vacuum to give 0.24 g(80%) of the title compound as a white powder; TLC, R_(f) =0.62 & 0.75,CHCl₃ : MeOH (95:5); HPLC, t_(R) =14.88 & 21.56, Col B, H₂ O: CH₃ CN:THF:TFA (55:35:15:0.1), FR=3.0.

Analysis calculated for: C₃₇ H₄₀ BrF₃ N₄ O₇ S.0.25H₂ O: C, 53.78; H,4.94; N, 6.78. Found: C, 53.84.; H, 4.98; N, 6.45.

EXAMPLE 109 3R(orS)-(Tricyclo[3.3.1.1³,7]dec-1-yl)sulfonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═1-adamantyl, R⁴ ═H,A═S(O₂), n=1)

From the flash chromatography described in Example 91c was obtained thetitle compound as the other substantially pure isomer (84%); HPLC, t_(R)=3.89, Col A, H₂ O:CH₃ CN (45:55), FR=2.0.

Analysis calculated for: C₂₆ H₄₀ F₃ N₃ O₅ S.0.5H₂ O: C, 54.57; H, 7.22;N, 7.34. Found: C, 54.52; H, 7.15; N, 7.33.

EXAMPLE 110 3S(orR)-[4-(Phenylsulfonylaminocarbonyl)phenylaminocarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³ ═4-[φS(O₂)NHC(O)]φ, R⁴═H, A═NHCO, n=1)

The two diastereomers of Example 58 were separated by MPLC on aLiChroprep® RP-8 column (Merck, Size B 40-63 μm) using MeOH:H₂ O (50:50)as eluent. The fractions collected were analyzed by HPLC, and theappropriate fractions were combined and lyophilized to give the titleproduct; HPLC, t_(R) =4.5, Col B, H₂ O: CH₃ CN:THF:TFA (55:35:15:0.1),FR=2.0.

EXAMPLE 111 3S(orR)-Phenylmethoxycarbonyl-L-phenylglycyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═φ, R³ ═φCH₂ --, R⁴ ═H, A═OCO, n=1)

Using the method of Example 61c, the product prepared by the method ofExample 92a was oxidized to afford, after purification by flashchromatography (MeOH:CH₂ Cl₂ (1.5:98.5)), the title product (80%) as onesubstantially pure isomer; TLC, R_(f) =0.26, pentane: MeOH:Et₂ O(25:1:99).

Analysis calculated for: C₂₇ H₃₀ F₃ N₃ O: C, 60.78; H, 5.67; N, 7.88.Found: C, 60.64; H, 5.85; N, 7.96.

EXAMPLE 1123R(orS)-Phenylmethoxycarbonyl-L-phenylglycyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═φ, R³ ═φCH₂ --, R⁴ ═H, A═OCO, n=1)

From the flash chromatography described in Example 111 was obtained thetitle product (83%) as the other substantially pure isomer; TLC, R_(f)=0.30, pentane:MeOH:Et₂ O (25:1:99).

Analysis calculated for: C₂₇ H₃₀ F₃ N₃ O₅ : C, 60.78; H, 5.67; N, 7.88.Found: C, 59.43; H, 5.65; N, 7.48.

EXAMPLE 1133R(orS)-[4-[(4-Bromophenyl)sulfonylaminocarbonyl]phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxo-pentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃,R² ═(CH₃)₂ CH--, R³═4-[4-(Brφ)S(O₂)NHC(O)]φ, R⁴ ═H, A═CO, n=1)

The product of Example 95b (0.5 g, 0.7 mmol) was chromatographed by MPLCon a LiChroprep® RP-8 column (Merck, size B 40-63 μm) using MeOH:H₂ O(60: 40) as eluent. The fractions collected were evaluated by HPLC,combined, and lyophilized to give two products. The title product (0.147g) was obtained as a substantially pure isomer; HPLC, t_(R) =12.38, ColB, H₂ O: CH₃ CN: T}{F: TFA (55: 35: 15:0.1), FR=3.0.

EXAMPLE 114 3S (orR)-[4-[(4-Bromophenyl)sulfonylaminocarbonyl]phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³═4-[(4-Brφ)S(O₂)NHC(O)]φ, R⁴ ═H, A═CO, n=1)

The other product obtained in the separation described in Example 113was the title product (0.065 g), obtained as a substantially pureisomer; HPLC, t_(R) =8.44, Col B, H₂ O:CH₃ CN:THF:TFA (55:35:15:0.1),FR=3.0.

EXAMPLE 115 3S(orR)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³═4-[(4-Clφ)S(O₂)NHC(O)]φ, R⁴ ═H, A═CO, n=1)

A portion of material prepared as described in Example 104 (544.8 mg)was dissolved in H₂ O:CH₃ CN: THF (2.2 m1:3.3 ml:0.5 ml) and wasseparated by MPLC on a Lobar® size B LiChroprep® RP-8 column using H₂ O:CH₃ CN:THF:TFA (55:32.5:12.5:0.1). After analysis by HPLC, theappropriate fractions were combined, concentrated under vacuum, anddried under high vacuum at 43° to afford the title compound (255 mg) asa white amorphous solid; HPLC, t_(R) =5.76, Col B, H₂ O:CH₃ CN:THF: TFA(55:32.5:12.5:0.1), FR=3.0.

Analysis calculated for: C₃₀ H₃₄ C₁ F₃ N₄ O₇ S.1.3H₂ O: C, 50.71; H,5.19; N, 7.89. Found: C, 50.88; H, 4.87: N, 7.70.

EXAMPLE 116 3R(orS)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]phenyl]carbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═(CH₃)₂ CH--, R³═4-[(4-Clφ)S(O₂)NHC(O)]φ, R⁴ ═H, A═CO, n=1)

A portion of material prepared as described in Example 104 (573.8 mg)was dissolved in H₂ O:THF (2 ml:3 ml) and was separated by MPLC on aLobar® size B LiChroprep® RP-8 column using THF:H₂ O:TFA (41:59:0.1) aseluent. After analysis by HPLC, the appropriate fractions were combinedand lyophilized to afford the title compound (51.8 mg) as asubstantially pure isomer (99:1 by HPLC); HPLC, t_(R) =8.8, Col B, H₂O:CH₃ CN: THF:TFA (55:32.5:12.5:0.1), FR=3.0.

EXAMPLE 117 3S(orR)-Phenylmethoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═φCH₂, R⁴ ═H, A═OCO,n=1)

A portion of material prepared according to the method of Example 11 (10g, 0.02 mol) was separated into its individual substantially opticallypure isomers by flash chromatography (1 kg of silica gel, Et₂ O:hexane(80:20)). Combination of the appropriate fractions afforded the titlecompound (3.17 g) as a substantially pure isomer; HPLC, t_(R) =5.65, ColA, H₂ O:CH₃ CN (55:45), FR=2.0.

Analysis calculated for: C₂₄ H₃₂ F₃ N₃ O₅.H₂ O: C, 55.47; H, 6.46; N,8.08. Found: C, 55.50; H, 6.77; N, 7.99.

EXAMPLE 118 3R(orS)-Phenylmethoxycarbonyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═CH₂, R⁴ ═H, A═OCO, n=1)

From the separation described in Example 117 combination of theappropriate fractions afforded the title compound (3.67 g) as the othera substantially pure isomer.

Analysis calculated for: C₂₄ H₃₂ F₃ N₃ O₅ : C, 57.71; H, 6.46; N, 8.41.Found: C, 57.61; H, 6.34; N, 7.96.

EXAMPLE 119 3S(orR)-[(4-Carboxyphenyl)aminocarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═4-(HOOC)φ, R⁴ ═H,A═NHCO, n=1)

A portion of a product prepared as described in Example 16 (500 mg) wasseparated by MPLC on a Lobar® size B LiChroprep® RP-8 column usingMeOH:H₂ O (1:1) as eluent. After analysis by HPLC, the appropriatefractions were combined to afford the title compound (150 mg) as asubstantially pure isomer; HPLC, t_(R) =6.58, Col A, CH₃ CN:H₂ O(25:75), FR=2.0.

EXAMPLE 120 3R(orS)-[(4-Carboxyphenyl)aminocarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═4-(HOOC)φ, R⁴ ═H,A═NHCO, n=1)

By combination of the appropriate fractions from the separationdescribed in Example 119, the title compound was obtained as a highlyenriched isomer (220 mg) in a ratio of 90.4:9.5 with the isomerdescribed in Example 119; HPLC, t_(R) =11.09, Col A, CH₃ CN:H₂ O(25:75), FR=2.0.

EXAMPLE 1213(RS)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═4-[(4-Clφ)S(O₂)NHCO]φ,R⁴ ═H, A═CO, n=1)

A preferred method for conversion of material prepared using the methodof Example 5d into the title compound is as follows:

a. 1,1-Dimethylethyl 4-[(4-chlorophenyl)sulfonylaminocarbonyl]benzoate

A 5-liter 3-neck round bottom flask was equipped with a mechanicalstirrer and nitrogen inlet. CH₂ Cl₂ (2 liters) was placed in thereaction flask and terephthalic acid mono-t-butyl ester (127.5 g, 0.574mol), DMAP (70.06 g, 0.574 mol), and 4-chlorobenzenesulfonamide (110.04g, 0.574 mol) were added in that order using CH₂ Cl₂ (400 ml) to washdown the solids. WSCDI (110.10 g, 0.574 mol) was added in portions over10 min using CH₂ Cl₂ (100 ml) to wash down the solid. After the reactionmixture was stirred overnight at room temperature, it was concentratedunder vacuum to dryness. The residue was partioned between EtOAc andwater. The EtOAc solution was washed (20% aq citric acid, satd aqNaHCO₃, brine), dried (Na₂ SO₄), and concentrated under vacuum to awhite solid. After drying in a vacuum oven at 50°, the title product(227 g, 100%) was obtained in a sufficiently pure state to be useddirectly for the next step; TLC, R_(f) =0.43, MeOH:CHCl₃ (15:85).(Further purification was possible by recrystallization from EtOH:water;m.p. above 300°).

b. 4-[(4-Chlorophenyl)sulfonylaminocarbonyl]benzenecarboxylic acid

A 3-liter 3-neck round bottom flask was equipped with a mechanicalstirrer and a CaCl₂ drying tube. TFA (1300 g) was added and cooled to 0°; and the product of Example 121a (79.5 g, 0.20 mol) was added.Initially, the solid dissolved, giving a clear solution. After 10-15min, a heavy precipitate of product formed, and it was difficult to stirthe reaction mixture. Vigorous stirring with the mechanical stirrer wasessential to drive the reaction to completion. The reaction mixture wasstirred at 0°-5° for 1 hr before it was poured onto 1500 ml of ice/waterand stirred for 2 hr. The resulting solid was filtered and dried. Thewhite solid (61.5 g, 91%) obtained was recrystallized from 1600 mlabsolute EtOH/1600 ml H₂ O to yield the title product (54 g, 80%) aswhite needles; m.p.=286°-288° ; TLC, R_(f) =0.7, MeOH:CHCl₃ : AcOH(10:90:1).

c.2(RS),3(SR)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide (Formula VIIb, R¹ ═CH(CH₃)CH₃, R²═CH(CH₃)CH₃, R³ ═4-[(4Cl-φ)S(O₂)NHCO]φ, R⁴ ═H, A═CO, n=1)

A 250 ml 3-neck round bottom flask was equipped with a magnetic stirrerand nitrogen inlet. To CH₂ Cl₂ (125 ml) in the reaction flask, theproduct of Example 121b (5.45 g, 16.07 mmol), DMAP (1.96 g, 16.07 mmol),and material prepared according to Example 5d (6.20 g, 16.87 mmol) wereadded using CH₂ Cl₂ (20 ml) to wash down the solids; then, WSCDI (3.24g, 16.87 mmol) was added using CH₂ Cl₂ (5 ml) to wash down the solid.After the reaction mixture had been stirred for 5 hr, it was washed (1NHCl, satd aq NaHCO₃, brine), dried (Na₂ SO₄), and concentrated undervacuum to afford a crude product (11.0 g, 100%) as a white solid. Aportion (3.39 g) of this crude product was dissolved in MeOH (40 ml) anddiluted with water (9 ml). The resulting solution was saturated with K₂CO₃ and stirred overnight at room temperature. After most of the MeOHhad been removed under vacuum, the residue was partitioned between EtOAcand water. The EtOAc solution was washed (satd aq NaHCO₃, brine), dried(Na₂ SO₄), and concentrated to afford a substantially pure title product(3.13 g, 92%); TLC, R_(f) =0.38 & 0.46, MeOH:CHCl₃ :AcOH (5:95:1); HPLC,t_(R) =6.20 & 6.25, Col A, H.sub. 2 O:CH₃ CN:THF:TFA (55:35:15:0.1),FR=3.0.

d.3(RS)-[4-[(4-Chlorophenyl)sulfonylaminocarbonyl]phenylcarbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃ , R³ ═4-[(4-Clφ)S(O₂)NHCO]φ,R⁴ ═H, A═CO, n=1)

To a stirred solution of Dess-Martin periodinane (636 g, 1.50 mol) inCH₂ Cl₂ (5 liter) was added product prepared using the method of Example121c (351 g, 0.50 mol) in THF (500 ml), and the resulting suspension wasdiluted with CH₂ Cl₂ (2 liter), followed by the addition of TFA (171 g,1.50 mol). After the reaction mixture had been stirred overnight at roomtemperature, the CH₂ Cl₂ was removed under vacuum, the residue wasdiluted with EtOAc and treated with a 1:1 mixture of satd aq NaHCO₃ andsatd aq Na₂ S₂ O₃. When all the solid had dissolved, the aq layer wasseparated and the EtOAc layer was washed (a mixture of satd aq NaHCO₃:satd aq Na₂ SO₃ (1:1), satd aq NaHCO₃, brine), dried (Na₂ SO₄) andconcentrated under vacuum. The residue was dissolved in MeOH (1.5 liter)and treated with 1N HCl (1.5 liter), and the MeOH was removed undervacuum. The aq suspension remaining was extracted with CH₂ Cl₂, and thecombined CH₂ Cl₂ extracts washed (brine), dried (Na₂ SO₄), andconcentrated under vacuum to afford, after purification by flashchromatography (gradient, Et₂ O to Et₂ O:MeOH (95:5)) and acidificationof the chromatographed product with MeOH 1N HCl as described above, thetitle product (37%); HPLC, t_(R) =6.68 & 9.27, Col B, H₂ O:CH₃CN:THF:TFA (55:35:15:0.1), FR=2.0.

Analysis calculated for: C₃₀ H₃₄ C₁ F₃ N₄ O₇ S: C, 52.44; H, 4.99; N,8.15. Found: C, 52.31; H, 5.20; N, 8.20.

EXAMPLE 122 3(RS)-N²,N⁶-Di(phenylmethoxycarbonyl)-L-lysyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ic, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═φCH₂, R⁴ ═H, R⁵ ═φCH₂OCONH(CH₂)₄, R⁶ ═H, A═OCO, n=1)

Using the method of Example 54b, the product of Example 28a was oxidizedto afford, after purification by flash chromatography (hexane:Et₂ O(1:1), then Et₂ O, then Et₂ O:EtOAc (3:1)), the title product (56%);HPLC, t_(R) =4.19 & 6.02, Col A, CH₃ CN:H₂ O (60:40), FR=1.5.

Analysis calculated for: C₃₈ H₅₀ F₃ N₅ O₈.0.5H₂ O: C, 59.21; H, 6.67; N,9.03. Found: C, 58.93; H, 6.62; N, 8.75.

EXAMPLE 1233(RS)-[1,4-Dioxo-4-(phenylsulfonylamino)butyl]-L-leucyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ic, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═φS(O₂)NHCO(CH₂)₂, R⁴═H, R⁵ ═(CH₂)₃ CH₃, R⁶ ═H, A═CO, n=1)

A solution of the product of Example 24 (0.5 g, 0.87 mmol),benzenesulfonamide (0.14 g, 0.87 mmol), DMAP (0 .11 g, 0.87 mmol) andDCC (0.18 g, 0.87 mmol) in CH₂ Cl₂ (20 ml) was stirred for four days atroom temperature. The reaction mixture was filtered and concentratedunder vacuum to give a crude product. The product was purified by flashchromatography on Baker pH 5.0 silica gel (gradient, CHCl₃ to MeOH:CHCl₃(2:98) to MeOH:CHCl₃ (5:95)) to give the title product (0.37 g); HPLC,t_(R) =3.84 & 5.03, Col A, H₂ O:CH₃ CN (65: 35), FR=1.0.

Analysis calculated for: C₃₂ H₄₆ F₃ N₅ O₈ S: C, 52.23; H, 6.57; N, 9.52.Found: C, 51.94; H, 6.29; N, 9.37.

EXAMPLE 1243(RS)-[4-(Methylsulfonylamino)-1,4-dioxobutyl]-L-leucyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ic, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═CH₃ S(O₂)NHCO(CH₂)₂, R⁴═H, R⁵ ═(CH₂)₃ CH₃, R⁶ ═H, A═CO, n=1)

A solution of the product of Example 24 (0.5 g, 0.87 mmol),methanesulfonamide (0.082 g, 0.87 mmol), DMAP (0.11 g, 0.87 mmol) andDCC (0.18 g, 0.87 mmol) in CH₂ Cl₂ (20 ml) was stirred for four days atroom temperature. The reaction was filtered and concentrated undervacuum to give a crude product which was partially purified by flashchromatography on Baker pH 5.5 silica gel (gradient, CHCl₃, MeOH:CHCl₃(1:99) to (2.5:97.5)). The partially purified product was partitionedbetween EtOAc and a mixture of aqueous 1N HCl and brine. The organicphase was dried (Na₂ SO₄), filtered, and concentrated to give the titleproduct (0.28 g); HPLC, t_(R) =5.99 & 8.95, Col A, H₂ O: CH₃ CN (65:35),FR=1.0.

Analysis calculated for: C₂₇ H₄₄ F₃ N₅ O₈ S: C, 49.46; H, 6.76; N,10.68. Found: C, 49.07; H, 6.79; N, 10.43.

EXAMPLE 125 3(RS)-N² -[1,4-Dioxo-4-(phenylsulfonylamino)butyl]-N⁶-phenylmethoxycarbonyl-L-lysyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ic, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═φS(O₂)NHCO(CH₂)₂, R⁴═H, R⁵ ═φCH₂ OCONH(CH₂)₄, R⁶ ═H, A═CO, n=1)

A solution of the product of Example 27 (493 mg, 0.670 mmol),benzenesulfonamide (117 mg, 0.745 mmol), DMAP (91 mg, 0.745 mmol), andDCC (153 mg, 0.745 mmol) in CH₂ Cl₂ (20 ml) was stirred at roomtemperature for 24 hr. The solution was diluted with EtOAc, washed(water), dried (MgSO₄), filtered, and concentrated under vacuum. Thecrude product was purified by flash chromatography on Baker pH 5.5silica gel (CH₃ OH:CHCl₃ (2.5:97.5)) to afford the title product (243mg) as a white powder; TLC, R_(f) =0.50, CH₃ OH:CHCl₃ :AcOH (5:94:1).

Analysis calculated for: C₄₀ H₅₃ F₃ N₆ O₁₀ S.0.75H₂ O: C, 54.56; H,6.24; N, 9.54. Found: C, 54.52; H, 6.23; N, 9.48.

EXAMPLE 126 3(RS)-[1,4-Dioxo-4-[(tricyclo[3.3.1.1³,7]dec-1-yl)sulfonylamino]butyl]-L-leucyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ic R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³═(1-adamantyl-S(O₂)NHCO(CH₂)₂, R⁴ ═H, R⁵ ═(CH₂)₃ CH₃, R⁶ ═H, A═CO, n=1)a. 1-Adamantanesulfinamide

To the product of Example 82a (10.0g, 45.7 mmol) was slowly added concammonium hydroxide (300 ml) and the mixture was heated to reflux forthree hr. After distillation of the ammonium hydroxide, the residue wastaken up in water and extracted with Et₂ O. The Et₂ O layer was washed(brine), dried (Na₂ SO₄), filtered, and concentrated under vacuum. Thecrude product was purified by suction chromatography on silica gel (Et₂O to EtOAc) to give the product (4.2g) as a white solid; m.p.139°-141°(Lit. 141°-142°).

b. 1-Adamantanesulfonamide

To a solution of the product of Example 126a (4.0 g, 20.0 mmol) inacetone (150 ml) at reflux was added a satd acetone solution of KMnO₄until a faint violet color persisted. The solution was cooled, filteredthrough Celite® and concentrated under vacuum to give the product (3.2g)as a solid; m.p.=191°-193° (Lit. 197°-198°); TLC, R_(f) =0.80, EtOAc.

c. 3(RS)-[1,4-Dioxo-4-[(tricyclo [3.3.1.1³,7]dec-1-yl)sulfonylamino]butyl]-L-leucyl-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ic, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³═(1-adamantyl)S(O₂)NHCO(CH₂)₂, R⁴ ═H, R⁵ ═(CH₂)₃ CH₃, R⁶ ═H, A═CO, n=1)

A solution of the product of Example 24 (300 mg, 0.51 mmol), DMAP (62mg, 0.51 mmol), WSCDI (99 mg, 0.51 mmol) and the product of Example 126b(110 mg, 0.51 mmol) in CH₂ Cl₂ (30 ml) was stirred at room temperaturefor 16 hr. The CH₂ Cl₂ solution was washed (1N HCl, brine), dried(MgSO₄), filtered, and concentrated under vacuum. The crude product waspurified by preparative TLC (MeOH:CHCl₃ (1:9)) to give the title productas a solid; TLC, R_(f) =0.56, MeOH:CHCl₃ (5:95); HPLC, t_(R) =4.23 &7.05, Col A, H₂ O:CH₃ CN (1:1), FR=2.0.

Analysis calculated for: C₃₆ H₅₆ F₃ N₅ O₈ S.1.2H₂ O: C, 54.22; H, 7.38;N, 7.78. Found: C, 54.28; H, 7.84; N, 7.71.

EXAMPLE 1273(RS)-[4-(Phenylcarbonylaminosulfonyl)phenyl]carbonyl-L-valyl-N-[3-(1,1,1-trifluor-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═4-[φCONHS(O₂)]φ--, R⁴═H, A═CO n=1) a. N-(4-Methylphenylsulfonyl)benzamide

p-Toluenesulfonyl isocyanate (1.00g, 5.07 mmol) was added to a reactionvessel containing A1Cl₃ (1.69 g, 12.68 mmol) and benzene (35 ml). Thereaction mixture was stirred under N₂ and at room temperature for 3.5hours before it was poured into crushed ice (100 ml) containing conc HCL(25 ml). The resulting mixture was stirred for 10 min and partitionedwith ether (100 ml). After the aqueous layer was separated, theremaining organic layer was washed with H₂ O (2×50 ml) and brine (1×50ml), dried (Na₂ SO₄) and concentrated in vacuo to give the crude product(1.40 g). Purification by ether trituration (200 ml) afforded 1.12 g(80%) of the product; TLC, R_(f) =0.68, CH₂ Cl₂ :MeOH:HOAc (94.5:5:0.5).

b. 4-(Phenylcarbonylaminosulfonyl)benzoic acid

Potassium permanganate (1.67g, 10.56 mmol) was added in four equalportions to a preheated reaction vessel (85°) containing the product ofExample 127a, (0.97 g, 3.52 mmol) and 0.25M MgSO₄ (70 ml). The reactionwas stirred at 85° for 2 hours. The hot reaction mixture was filteredthrough diatomaceous earth and acidified to pH 4.0 with 20% H₂ SO₄. Theproduct, which precipitated out of solution as a white powder, wasfiltered, washed with cold H₂ O (100 ml) and dried under high vacuumovernight to afford 1.00g (93%); TLC, R_(f) =0.34, CH₂ Cl₂ :MeOH:HOAc(94.5; 5:0.5).

c.2(RS),3(SR)-[4-(Phenylcarbonylaminosulfonyl)phenyl]carbonyl-L-valyl-N-[3-(1,1,1-trifluoro-2-hydroxy-4-methylpentyl)]-L-prolinamide(Formula VIIb, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═4-[φCONHS(O₂)]φ--, R⁴═H, A═CO, n=1)

WSCDI (0.47 g, 2.45 mmol) was added to a reaction vessel containing theproduct of Example 127b (0.62 g, 2.04 mmol), the product of Example 5d(0.75 g, 2.04 mmol), HOBT (0.33 g, 2.45 mmol) and dry THF:DMF (8:1, 40ml). The reaction was stirred overnight under N₂ and at room temperaturebefore it was concentrated in vacuo and the resulting syrup wasredissolved in CH₂ Cl₂. The organic phase was washed with 1N HCl (2×50ml) and brine (1×50ml), dried (Na₂ SO₄) and concentrated in vacuo togive the crude product (1.38 g). The crude product was purified by flashchromatography on acidic silica gel, eluting with MeOH:CH₂ Cl₂ (5:95) togive 1.17 g (87.31%) of the product; TLC, R_(f) =0.21-0.32, CH₂ Cl₂:MeOH:HOAc (94.5:5:0.5).

d.3(RS)-[4-(Phenylcarbonylaminosulfonyl)phenyl]carbonyl-L-valyl-N-[3-(1,1,1-trifluor-4-methyl-2-oxopentyl)]-L-prolinamide(Formula Ib, R¹ ═CH(CH₃)CH₃, R² ═CH(CH₃)CH₃, R³ ═4-[φCONHS(O₂)]φ--, R⁴═H, A═CO, n=1)

TFA (261 mg, 176 ul, 2.29 mmol) was added to a reaction vesselcontaining the product of Example 127c, (600 mg, 0.92 mmol), Dess-Martinperiodinane (972 mg, 2.29 mmol) and CH₂ Cl₂ (30 ml). The reactionmixture was stirred under N₂ and at room temperature overnight. Thereaction mixture was partitioned between EtOAc (75 ml) and satd NaHCO₃(50 ml) containing Na₂ S₂ O₃ (2.53 g, 16.03 mmol). After the organiclayer was separated, the remaining aqueous layer was acidified to pH 2.0with 6N HCl. The aqueous layer wa extracted with CH₂ Cl₂. The CH₂ Cl₂solution was concentrated in vacuo to give the crude product (300 mg),which was purified by dissolving it in ether and reprecipitating theproduct with hexane to afford 123 mg , (20.5%); TLC, R_(f) =0.30-0.43,CH₂ Cl₂ :MeOH: HOAc (94. 5:5:0.5).

Analysis calculated for: C₃₀ H₃₅ F₃ N₄ O₇ S.2.5 H₂ O: C, 51.64; H, 5.78;N, 8.03. Found: C, 51.31; H, 5.14; N, 8.12.

Alternatively, the title product may be prepared by coupling benzoicacid with3(RS)-[4-aminosulfonylphenyl)carbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamideusing a similar procedure to the one described in Example 89. Thesulfonamide was prepared as follows:

e.2(RS),3(SR)-[(4-Aminosulfonylphenyl)carbonyl]-L-valyl-N-[3-(2-hydroxy-4-methyl-1,1,1-trifluoropentyl)]-L-prolinamide

To a reaction vessel containing 4-carboxybenzene sulfonamide (1.24 g,6.16 mmol), the product of Example 5d (1.49 g, 4.06 mmol), DMAP (0.60 g,4.88 mmol) and DMF:CH₂ Cl₂ (1:1, 40 ml) was added WSCDI (0.94 g, 4.88mmol). The reaction was stirred overnight under N₂ and at roomtemperature before it was washed with 1N HCl (2×50 ml) and brine (1×50ml), dried (Na₂ SO₄), and concentrated under vacuum to give the crudeproduct (3.11 g). The crude product was purified by flash chromatographyon acidic silica gel (MeOH:CH₂ Cl₂ (15:85)) to afford the pure product(0.52 g, 24.8%); TLC, R_(f) =0.49-0.65, CH₂ Cl₂ :MeOH:HOAc(89.5:10:0.5).

f.3(RS)-[(4-Aminosulfonylphenyl)carbonyl]-L-valyl-N-[3-(1,1,1-trifluoro-4-methyl-2-oxopentyl)]-L-prolinamide

To a reaction vessel containing the product of Example 127e (250 mg,0.454 mmol), Dess-Martin periodinane (324 mg, 0.76 mmol) and CH₂ Cl₂ (10ml) was added TFA (86.7 mg, 0.76 mmol, 58.5 μl). After the reaction wasstirred under N₂ and at room temperature for 3 hours, it was partitionedbetween EtOAc (50 ml) and satd NaHCO₃ (50 ml) containing Na₂ S₂ O₃ (841mg, 5.32 mmol). After the organic phase was separated, the aqueous layerwas extrated with EtOAc (2×50 ml). The combined organic phase was washedwith brine (2×50 ml), dried (Na₂ SO₄), and concentrated under vacuum toprovide a crude product (230 mg). The crude product was purified byflash chromatography (acidic silica gel; MeOH:CH₂ Cl₂ (10:90)) to givepure product (180 mg, 72.3%); TLC, R_(f) =0.60-0.69, MeOH:CH₂ Cl₂(10:90).

Analysis calculated for: C₂₃ H₃₁ F₃ N₄ O₆ S.0.5 H₂ O: C, 49.54; H, 5.78;N, 10.05. Found: C, 49.53; H, 5.77; N, 9.51.

What is claimed is:
 1. A compound of the formula V ##STR5## wherein R¹is an alkyl group containing 1 to 5 carbon atoms and the acid-additionsalts thereof.
 2. A compound as claimed in claim 1 wherein R¹ isisopropyl, and the acid addition salts thereof.